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

Abstract

Background: Cerebrospinal 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.

Methods: In 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 Aβ(1-37), Aβ(1-38), Aβ(1-40), and Aβ(1-42) levels were analyzed.

Results: Increases 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.

Conclusions: CSF 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 registration: ClinicalTrials.gov NCT01436188 . Registered 15 September 2011.

Keywords: Alzheimer’s disease; Aβ peptides; Catheterization; Cerebrospinal fluid; Sampling frequency.

Fig. 1

Study design. Arrows indicate time points of CSF sampling post spinal catheter placement. Cohort 1 and Cohort 3: 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 20, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 30, 32, 34, and 36 h. Cohort 2: 0, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 16, 20, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 30, 32, 34, and 36 h. Cohort 4: 0, 2, 4, 8, 24, 28, and 36 h. Per time point, 6 ml of CSF was collected for cohorts 1–3 and 4 ml was collected for cohort 4. LP lumbar puncture

Fig. 2

Mean % change from baseline of CSF Aβ_1–40 for all cohorts. Standard deviation is not shown for clarity of representation. Individual profiles can be found in Fig. 3. Cohort 1: immediate sampling, high frequency; cohort 2: delayed sampling, high frequency, procedure effect; cohort 3: ibuprofen, high frequency, inflammation effect; cohort 4: immediate sampling, low frequency. Aβ amyloid beta

Fig. 3

Individual CSF Aβ_1–40 profiles for all participants per cohort. a Cohort 1: immediate sampling, high frequency. b Cohort 2: delayed sampling, high frequency, procedure effect. c Cohort 3: ibuprofen, high frequency, inflammation effect. d Cohort 4: immediate sampling, low frequency. APOE ε4 carriers are indicated in red with a square or diamond symbol. Cohort 1: only five participants are shown; one participant (participant 6) did not have a baseline sample available. Aβ amyloid beta (Color figure online)