title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01436188 . Registered 15 September 2011.
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium.
authors.forename: Bianca
authors.initials: B
authors.lastname: Van Broeck
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium.|Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Timmers
authors.affiliation: SGS Life Science Services, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ramael
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bogert
authors.affiliation: University of Pennsylvania Medical Center, Philadelphia, PA, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: John
authors.initials: J
authors.lastname: Slemmon
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Nueten
authors.affiliation: Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium. jstreffe@its.jnj.com.|Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. jstreffe@its.jnj.com.
authors.forename: Johannes Rolf
authors.initials: JR
authors.lastname: Streffer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D002404:Catheterization; D002408:Catheters, Indwelling; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D013129:Spinal Puncture; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; Aβ peptides; Catheterization; Cerebrospinal fluid; Sampling frequency