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

作者：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; Sjogren Magnus; Margolin Richard; Chen Xia; Farlow Martin R; Dean Robert A; Waring Jeffrey F

来源：Alzheimer's Research and Therapy, 2015, 7(1): 53.

DOI：10.1186/s13195-015-0136-z

Introduction: Amyloid-beta (A beta) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) A beta 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 A beta variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF A beta concentrations over time.
Methods: Grouped analysis of CSF A beta 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 A beta concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for A beta 40 and A beta 42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of A beta concentrations over time.
Results: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of A beta 40 and A beta 42 as well as an A beta diurnal pattern in all of the sponsors' studies. In contrast, A beta 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 A beta 40 and A beta 42 concentrations during the first 6 hours of collection.
Conclusions: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring A beta levels and keeping the frequency standardized between experimental groups. The A beta diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging A beta 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 A beta over 24-48 hours, but factors affecting A beta concentration such as linear rise and diurnal variation need to be accounted for in planning study designs.

• 出版日期2015-7-29
• 单位上海市精神卫生中心