An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter

Brendan P. Lucey, Celedon Gonzales, Ujjwas Das, Jinhe Li, Eric R. Siemers, J. Randall Slemmon, Randall J. Bateman, Yafei Huang, Gerard B. Fox, Jurgen A H R Claassen, Diane Slats, Marcel M. Verbeek, Gary Tong, Holly Soares, Mary J. Savage, Matthew Kennedy, Mark Forman, Magnus Sjögren, Richard Margolin, Xia Chen & 3 others Martin Farlow, Robert A. Dean, Jeffrey F. Waring

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number53
JournalAlzheimer's Research and Therapy
Volume7
Issue number1
DOIs
StatePublished - Jul 29 2015

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Indwelling Catheters
Spinal Puncture
Amyloid
Cerebrospinal Fluid
Analysis of Variance
Catheters
Pharmaceutical Preparations
Artifacts
Observational Studies
Industry
Biomarkers
Enzyme-Linked Immunosorbent Assay
Placebos
Clinical Trials

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Cognitive Neuroscience

Cite this

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter. / Lucey, Brendan P.; Gonzales, Celedon; Das, Ujjwas; Li, Jinhe; Siemers, Eric R.; Slemmon, J. Randall; Bateman, Randall J.; Huang, Yafei; Fox, Gerard B.; Claassen, Jurgen A H R; Slats, Diane; Verbeek, Marcel M.; Tong, Gary; Soares, Holly; Savage, Mary J.; Kennedy, Matthew; Forman, Mark; Sjögren, Magnus; Margolin, Richard; Chen, Xia; Farlow, Martin; Dean, Robert A.; Waring, Jeffrey F.

In: Alzheimer's Research and Therapy, Vol. 7, No. 1, 53, 29.07.2015.

Research output: Contribution to journalArticle

Lucey, BP, Gonzales, C, Das, U, Li, J, Siemers, ER, Slemmon, JR, Bateman, RJ, Huang, Y, Fox, GB, Claassen, JAHR, Slats, D, Verbeek, MM, Tong, G, Soares, H, Savage, MJ, Kennedy, M, Forman, M, Sjögren, M, Margolin, R, Chen, X, Farlow, M, Dean, RA & Waring, JF 2015, 'An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter', Alzheimer's Research and Therapy, vol. 7, no. 1, 53. https://doi.org/10.1186/s13195-015-0136-z
Lucey, Brendan P. ; Gonzales, Celedon ; Das, Ujjwas ; Li, Jinhe ; Siemers, Eric R. ; Slemmon, J. Randall ; Bateman, Randall J. ; Huang, Yafei ; Fox, Gerard B. ; Claassen, Jurgen A H R ; Slats, Diane ; Verbeek, Marcel M. ; Tong, Gary ; Soares, Holly ; Savage, Mary J. ; Kennedy, Matthew ; Forman, Mark ; Sjögren, Magnus ; Margolin, Richard ; Chen, Xia ; Farlow, Martin ; Dean, Robert A. ; Waring, Jeffrey F. / An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter. In: Alzheimer's Research and Therapy. 2015 ; Vol. 7, No. 1.
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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.",
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T1 - An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter

AU - Lucey, Brendan P.

AU - Gonzales, Celedon

AU - Das, Ujjwas

AU - Li, Jinhe

AU - Siemers, Eric R.

AU - Slemmon, J. Randall

AU - Bateman, Randall J.

AU - Huang, Yafei

AU - Fox, Gerard B.

AU - Claassen, Jurgen A H R

AU - Slats, Diane

AU - Verbeek, Marcel M.

AU - Tong, Gary

AU - Soares, Holly

AU - Savage, Mary J.

AU - Kennedy, Matthew

AU - Forman, Mark

AU - Sjögren, Magnus

AU - Margolin, Richard

AU - Chen, Xia

AU - Farlow, Martin

AU - Dean, Robert A.

AU - Waring, Jeffrey F.

PY - 2015/7/29

Y1 - 2015/7/29

N2 - 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.

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