@article{b158abac84504e78852b703f59f8de09,
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 = "Introduction: 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.",
author = "Lucey, {Brendan P.} and Celedon Gonzales and Ujjwas Das and Jinhe Li and Siemers, {Eric R.} and Slemmon, {J. Randall} and Bateman, {Randall J.} and Yafei Huang and Fox, {Gerard B.} and Claassen, {Jurgen A.H.R.} and Diane Slats and Verbeek, {Marcel M.} and Gary Tong and Holly Soares and Savage, {Mary J.} and Matthew Kennedy and Mark Forman and Magnus Sj{\"o}gren and Richard Margolin and Xia Chen and Farlow, {Martin R.} and Dean, {Robert A.} and Waring, {Jeffrey F.}",
note = "Funding Information: This publication was supported by the Washington University Institute of Clinical and Translational Sciences grants UL1 TR000448 and KL2 TR000450 from the National Center for Advancing Translational Sciences (to BPL). The funding source had no role in the study design, data collection, management, analysis, interpretation of the data, or manuscript preparation. The work was supported by grants from the US National Institutes of Health (K08 AG027091-01, K23 AG 0309601, 2-R-01-NS065667-05, P50 AG05681-22, and P01 AG03991-22), Washington University Clinical & Translational Science Award UL1 RR024992, grants from an anonymous foundation, a gift from Betty and Steve Schmid, The Knight Initiative for Alzheimer Research, The James and Elizabeth McDonnell Fund for Alzheimer Research, and a research grant from Eli Lilly for the purchase of antibodies (to RJB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding sources had no role in the study design, data collection, management, analysis, interpretation of the data, or manuscript preparation This study was supported by Schering-Plough Research Institute, Kenilworth, NJ, USA, presently Merck Research Labs. They had no involvement in the collection and interpretation of data, or in the writing of the report. This work was also supported by the CAVIA project (number 733050202), which has been made possible by ZonMW, part of the Dutch national “{\textquoteleft}Deltaplan for Dementia{\textquoteright}: zonmw.nl/dementiaresearch” (Verbeek). For the original studies supported by Bristol-Myers Squibb, the company was the funding source and was involved in the study design, data collection, management, analysis, and interpretation of the data (HS, GT, JRS). However, the funding source was not involved in the study design, management, analysis, interpretation of the data, or manuscript preparation of this work. Bristol-Myers Squibb reviewed and approved the manuscript for publication. For original studies supported by AbbVie, Inc., the company was the funding source and was involved in the study design, data collection, management, analysis, and interpretation of the data (UD, JL, GBF, JFW). However, the funding source was not involved in the study design, management, analysis, interpretation of the data, or manuscript preparation of this work. AbbVie, Inc. reviewed and approved the manuscript for publication. For original studies supported by Eli Lilly and Company, the company was the funding source and was involved in the study design, data collection, management, analysis, and interpretation of the data (CG, ERS, MRF, RAD). However, the funding source was not involved in the study design, management, analysis, interpretation of the data, or manuscript preparation of this work. Eli Lilly and Company reviewed and approved the manuscript for publication. For original studies supported by Merck, the company was the funding source and was involved in the study design, data collection, management, analysis, and interpretation of the data (MJS, MK, MF, MS, RM, XC). However, the funding source was not involved in the study design, management, analysis, interpretation of the data, or manuscript preparation of this work. Merck reviewed and approved the manuscript for publication. Funding Information: BPL reports no conflicts of interest with the present work; outside the submitted work, he has served as a consultant for Neurim Pharmaceuticals. CG is a full-time employee of Eli Lilly and Company and holds stock in the company. UD was a former full-time employee of AbbVie Inc. and may hold stock in the company. JL is a full-time employee of AbbVie Inc. and holds stock in the company. ERS is a full-time employee of Eli Lilly and Company and holds stock in the company. JRS is a full-time employee of Johnson and Johnson; at the time of the study, he was a full-time employee of Bristol-Myers Squibb and holds stock in the company. RJB reports no conflicts of interest with the present work; outside the submitted work, he reports grants from the Alzheimer{\textquoteright}s Association, American Academy of Neurology, Anonymous Foundation, AstraZeneca, BrightFocus Foundation, Cure Alzheimer{\textquoteright}s Fund, Glenn Foundation for Medical Research, Merck, Metropolitan Life Foundation, NIH, Pharma Consortium (Biogen Idec, Elan Pharmaceuticals Inc., Eli Lilly and Co., Hoffman La-Roche Inc., Genentech Inc., Janssen Alzheimer Immunotherapy, Mithridion Inc., Novartis Pharma AG, Pfizer Biotherapeutics R&D, Sanofi-Aventi, Eisai), Roche, and the Ruth K. Broadman Biomedical Research Foundation; he has received nonfinancial support from Avid Radiopharmaceuticals; he is co-owner of C2N Diagnostics; he reports personal fee and nonfinancial support from Washington University, Roche, IMI, Sanofi, Global Alzheimer's Platform, FORUM, OECD, Boehringer Ingelheim, and Merck; and he also has intellectual property licensed to Washington University. YH reports no conflicts of interest. GBF is a full-time employee of AbbVie Inc. and holds stock in the company. JAHRC reports no conflicts of interest. DS reports no conflicts of interest. MMV reports no conflicts of interest with the present work; outside the submitted work, he has served as a consultant for Roche. GT is currently a full-time employee of Lundbeck; he was a full-time employee of Bristol-Myers Squibb, the sponsor of the BMS study, at the time when this work was done; he also owns in excess of $10,000 of company stock; but he reports no other conflicts of interest, including consultancies, honoraria, and paid expert testimony. HS is a full-time employee of Bristol-Myers Squibb. MJS is a full-time employee of Merck. MK is a full-time employee of Merck. MF is a full-time employee of Merck. MS was a full-time employee of Merck, the sponsor of the Merck studies, at the time when this work was done. RM is currently a full-time employee of CereSpir, Inc.; he was a full-time employee of Merck, the sponsor of the Merck studies, at the time when this work was done. XC is currently a full-time employee of Boehringer-Ingelheim; she was a full-time employee of Merck, the sponsor of the Merck studies, at the time when this work was done. MRF reports grant support and personal fees from Eli Lilly; he also reports personal fees from Merck; outside the submitted work, he has received grant support from Accera, Biogen, Eisai, Genentech, Roche, Lundbeck, and Chase Pharmaceuticals and personal fees from Eisai, Pfizer, Forest, Novartis, Accera, Alltech, Avanir, Biogen, FORUM Pharmaceuticals, Genentech, Grifols, Helicon, Inc. Research, Lundbeck, Medavante, Medivation, Neurotrope Biosciences, Prana Biotech, QR Pharma, Roche, Sanofi-Aventis, Schering-Plough, Toyama Pharm., and UCB Pharma; and he also has intellectual property licensed to Elan. RAD is a full-time employee of Eli Lilly and Company and holds stock in the company. JFW is a full-time employee of AbbVie Inc. and holds stock in the company. Publisher Copyright: {\textcopyright} 2015 Lucey et al.",
year = "2015",
month = jul,
day = "29",
doi = "10.1186/s13195-015-0136-z",
language = "English",
volume = "7",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
number = "1",
}