title: An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter.
abstract: BACKGROUND
  Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time.
  
  
  METHODS
  Grouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time.
  
  
  RESULTS
  Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors' studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection.
  
  
  CONCLUSIONS
  Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs.
authors.affiliation: Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St Louis, MO 63110 USA ; Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St Louis, MO 63110 USA.
authors.forename: Brendan P
authors.initials: BP
authors.lastname: Lucey
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, 893 South Delaware Avenue, Indianapolis, IN 46285 USA.
authors.forename: Celedon
authors.initials: C
authors.lastname: Gonzales
authors.affiliation: AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 6004 USA.
authors.forename: Ujjwas
authors.initials: U
authors.lastname: Das
authors.affiliation: AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 6004 USA.
authors.forename: Jinhe
authors.initials: J
authors.lastname: Li
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, 893 South Delaware Avenue, Indianapolis, IN 46285 USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Siemers
authors.affiliation: Johnson and Johnson, One Johnson & Johnson Plaza, New Brunswick, NJ 08933 USA.
authors.forename: J Randall
authors.initials: JR
authors.lastname: Slemmon
authors.affiliation: Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St Louis, MO 63110 USA ; Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St Louis, MO 63110 USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
authors.affiliation: Department of Medicine, St. Luke's Hospital, 232 South Woodsmill Road, Chesterfield, MO 63017 USA.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 6004 USA.
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.affiliation: Department of Geriatric Medicine, Donders Institute for Brain, Cognition, and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Route 925, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Jurgen A H R
authors.initials: JA
authors.lastname: Claassen
authors.affiliation: Department of Geriatric Medicine, Donders Institute for Brain, Cognition, and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Route 925, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Diane
authors.initials: D
authors.lastname: Slats
authors.affiliation: Department of Neurology, 830 TML, Neurochemistry Lab, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Verbeek
authors.affiliation: Lundbeck LLC, Four Parkway North, Deerfield, IL 60015 USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.affiliation: Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534 USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Soares
authors.affiliation: Merck and Company, RY50-1D-131, 126 East Lincoln Avenue, PO Box 2000, Rahway, NJ 07065 USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Savage
authors.affiliation: Merck and Company, 33 Avenue Louis Pasteur, Boston, MA 02115 USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kennedy
authors.affiliation: Merck and Company, 2000 Galloping Hill Road, Kenilworth, NJ 07033 USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Forman
authors.affiliation: Mental Health Centre Ballerup, Capital Region of Denmark, Maglevanget 2, 2750, Ballerup, Denmark.
authors.forename: Magnus
authors.initials: M
authors.lastname: Sjögren
authors.affiliation: CereSpir, Inc., 41 Madison Avenue, 31st Floor, New York, NY 10010 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Margolin
authors.affiliation: Boeringher Ingelheim, 900 Ridgebury Road, Ridgefield, CT 06877 USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurology, Indiana University School of Medicine, Goodman Hall, Suite 4700, 355 West 16th Street, Indianapolis, IN 46202 USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, 893 South Delaware Avenue, Indianapolis, IN 46285 USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.affiliation: AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL 6004 USA.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000704:Analysis of Variance; D002408:Catheters, Indwelling; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D017440:Photoperiod; D015203:Reproducibility of Results; D013129:Spinal Puncture / Q000295:instrumentation / Q000379:methods*; D013997:Time Factors; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)