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      Impact of frequent cerebrospinal fluid sampling on Aβ levels: systematic approach to elucidate influencing factors

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          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.

          Trial registration

          ClinicalTrials.gov NCT01436188. Registered 15 September 2011.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13195-016-0184-z) contains supplementary material, which is available to authorized users.

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          Most cited references8

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          Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker.

          To investigate the stability and time course of human CSF amyloid-beta (Abeta) levels over hours. Fifteen nondemented participants had CSF sampled hourly for up to 36 hours via indwelling lumbar catheter. CSF Abeta(1-x), Abeta(1-40), and Abeta(1-42) were measured by ELISA in each hourly CSF sample. Significant variation in Abeta levels of 1.5- to fourfold was detected over 36 hours of serially sampling in individual subjects. Abeta(40), Abeta(42), and Abeta(1-X) are highly correlated over time indicating that similar processes likely regulate the level of these species. On average, the fluctuations of Abeta levels appear to be time of day or activity dependent. Diagnostic and therapeutic trials that measure Abeta should control for the time of CSF sampling to minimize variability.
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            γ-secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes.

            According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ secretase shifting its cleavage activity from longer to shorter β-amyloid species without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aβ brain pathology and learning depend on their activity on γ-secretase or on other biological targets. The most studied γ-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aβ in the cerebrospinal fluid of healthy humans. Unfortunately, two large Phase 3 clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of APP, or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R flurbiprofen), a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch-sparing γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks.
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              Effect of human cerebrospinal fluid sampling frequency on amyloid-β levels.

              β-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aβ levels; we attempt to reconcile these conflicting observations. The current study examined the Aβ levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies. The results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aβ levels, and that lowering the CSF sampling frequency may help minimize this effect. These results will help guide clinical trial design for Alzheimer's disease therapy. Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                bvbroec1@its.jnj.com
                mtimmer3@its.jnj.com
                steven.ramael@sgs.com
                jbogert9@its.jnj.com
                leslie.shaw2@uphs.upenn.edu
                mmercken@its.jnj.com
                jslemmon@its.jnj.com
                lvnueten@its.jnj.com
                sebastiaan.engelborghs@uantwerpen.be
                +321-460-8745 , jstreffe@its.jnj.com
                Journal
                Alzheimers Res Ther
                Alzheimers Res Ther
                Alzheimer's Research & Therapy
                BioMed Central (London )
                1758-9193
                19 May 2016
                19 May 2016
                2016
                : 8
                : 21
                Affiliations
                [ ]Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium
                [ ]SGS Life Science Services, Antwerp, Belgium
                [ ]Janssen Research & Development, LLC, Raritan, NJ USA
                [ ]University of Pennsylvania Medical Center, Philadelphia, PA USA
                [ ]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
                Article
                184
                10.1186/s13195-016-0184-z
                4875639
                27206648
                85be33cb-3777-42fd-8205-ed04d798aea1
                © Van Broeck et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 December 2015
                : 11 April 2016
                Funding
                Funded by: Funding support by Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium.
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Neurology
                aβ peptides,alzheimer’s disease,catheterization,cerebrospinal fluid,sampling frequency

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