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Diurnal oscillation of CSF Aβ and other AD biomarkers
Molecular Neurodegeneration volume 12, Article number: 36 (2017)
To assess stages of Alzheimer's disease (AD) pathogenesis and the efficacy of drugs during clinical trials, there has been immense interest in the field to establish baseline cerebrospinal fluid (CSF) concentrations for potential AD biomarkers such as amyloid-β (Aβ) and tau. Significant within-person variations in CSF Aβ concentrations over time found that this variation followed the sleep-wake cycle. A recent paper in Molecular Neurodegeneration reported the absence of diurnal variations in multiple classical and candidate AD biomarkers, such as soluble APP, Aβ, tau, p-tau, YKL-40, VILIP-1, or apolipoprotein E. This commentary addresses these apparently discordant results regarding the diurnal variability of APP and Aβ compared with the literature. Despite our concerns, we appreciate the authors' interest in this important topic and contribution to improve our knowledge about the factors influencing Aβ diurnal variation.
To assess stages of Alzheimer’s disease (AD) pathogenesis and the efficacy of drugs during clinical trials, there has been immense interest in the field to establish baseline cerebrospinal fluid (CSF) concentrations for potential AD biomarkers such as amyloid-β (Aβ) and tau. For instance, lumbar punctures performed in individuals demonstrate low levels of Aβ42 in individuals cerebral with amyloid deposition . Large fluctuations in Aβ levels also were noted in individuals over years when sampled by lumbar puncture . Indwelling lumbar catheters have also been used to obtain more frequent CSF sampling over 24–48 h to understand Aβ metabolism for pharmacological modeling during drug trials. These catheter studies found significant within-person variability in CSF Aβ concentrations over the sampled time .
After Aβ release was demonstrated to be driven by neuronal activity in vivo , further investigations in rodents and humans found that the central nervous system concentration of Aβ fluctuated with the sleep-wake cycle. The amplitude of Aβ oscillation was decreased by both amyloid deposition in the brains of AD mouse models and humans, and in individuals with autosomal dominant AD mutations [5–7]. Soluble amyloid precursor protein (APP) and plasma Aβ also oscillate with sleep-wake activity [8, 9]. An analysis of serial Aβ concentrations from 178 participants who underwent CSF sampling via indwelling lumbar catheters in multiple academic and industry studies found an Aβ diurnal pattern in 16 of 17 studies . The only study without a diurnal oscillation was confounded by a bacterial filter placed on the catheter during collection that removed Aβ from the CSF samples . The Aβ diurnal pattern has also been replicated using different assays (enzyme-linked immunosorbent assay and mass spectrometry) .
Recently, Cicognola et al.  reported the absence of diurnal variations in multiple classical and candidate AD biomarkers, such as soluble APP, Aβ, tau, p-tau, YKL-40, VILIP-1, or apolipoprotein E. The authors sampled from 13 neurosurgical patients by either ventricular or lumbar CSF drainage at six time points over a 24-h period: 08:00, 12:00, 16:00, 20:00, 00:00, and 08:00. Four ml of CSF was collected at each time point.
Several factors may have led to the apparently discordant results regarding the diurnal variability of APP and Aβ, compared with the literature, in the Cicognola et al. study. First, it is possible that neurosurgical patients may have disrupted sleep-wake cycles that might alter diurnal patterns, particularly if the patients were sampled while in intensive care units where sleep would be fragmented due to frequent interruptions for clinical care. Further, brain tumors, hydrocephalus, and other intracranial pathologies could independently disturb sleep-wake activity and CSF flow.
Second, a longer sampling period may be necessary to observe fluctuations of Aβ in this population. For example, sampling periods up to 168 h were required to correlate Aβ fluctuations with changes in neurological status in patients with brain injury .
Third, the authors collected CSF from two different types of drains. Presumably, CSF was collected during the patients’ routine clinical care between the research sampling time points. Previous reports have found that more frequent sampling will increase the rate of linear rise in Aβ [10, 15]. The authors do not record how much CSF was drained between these time points for clinical purposes to control for this effect.
Fourth, we expect that CSF sampling was not frequent enough to detect an Aβ oscillation over 24 h and that the study is underpowered to detect any oscillation that may be present in this patient population.
Fifth, a repeated measures ANOVA may not be the correct test to determine if there is a diurnal oscillation as we would predict Aβ concentrations to oscillate together over the 24 h day.
Understanding how Aβ concentrations change over short periods of time (e.g. hours) in the human central nervous system is critical to the design and implementation of anti-Aβ AD treatment trials. Despite our concerns, we appreciate the authors’ interest in this important topic and contribution to improve our knowledge about the factors influencing Aβ diurnal variation.
Author’s response: Is there an association of diurnal variation with cerebrospinal fluid biomarkers for Alzheimer’s disease?
Claudia Cicognola1,2, Davide Chiasserini3, Paolo Eusebi3, Ulf Andreasson1,2, Hugo Vanderstichele4, Henrik Zetterberg1,2,5, Lucilla Parnetti3, Kaj Blennow1,2
1Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
2Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital Mölndal, SE-431 80 Mölndal, Sweden
3Section of Neurology, Department of Medicine, Center for Memory Disturbances, University of Perugia Sant’ Andrea delle Fratte, 06132 Perugia, Italy
4ADx NeuroSciences, Gent, Belgium
5UCL Institute of Neurology, Queen Square, London, UK
We thank Lucey and co-workers  for their interest in our paper . The authors point out some potential confounders that may influence sleep-wake cycles and variability of biomarkers for Alzheimer’s disease pathophysiology, thereby affecting the possibility to identify diurnal patterns of variation in biomarker concentrations . As acknowledged in the discussion section of our paper, these types of potential confounders may underlie the inconsistencies in outcomes between studies, as also recently reviewed . For example, acute brain trauma  and other possible disease- or drug-related effects on brain functioning and Aβ metabolism in neurosurgical patients ([13, 14] = Brody), may give different results than studies in healthy controls [10, 19]. Further, sampling procedures, e.g., the use of lumbar or ventricular catheters [10, 13, 19] or intracerebral microdialysis catheters , or even plasma , reflect different compartments that will impact the results.
Undoubtedly, we need to perform more studies using highly standardized protocols, controlling for clinical confounder as well possible artefacts due to variable sampling time-points and volume-related disturbances in CSF dynamics , to resolve whether Aβ and other biomarkers reflecting AD pathophysiology vary with the normal sleep-wake cycle, and show a true diurnal variation.
Analysis of variance
Amyloid precursor protein
Fagan AM, Mintun MA, Mach RH, Lee S-Y, Dence CS, Shah AR, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Amyloid-beta-42 in humans. Ann Neurol. 2006;59(3):512–9.
Kanai M, Matsubara E, Isoe K, Urakami K, Nakashima K, Arai H, et al. Longitudinal study of cerebrospinal fluid levels of tau, Aβ1-40, and Aβ1-42(43) in Alzheimer's disease: a study in Japan. Ann Neurol. 1998;44:17–26.
Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-β levels: implications for a diagnostic and therapeutic biomarker. Neurology. 2007;68:666–9.
Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, et al. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron. 2005;48:913–22.
Kang J-E, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, et al. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009;326(5955):1005–7. Pubmed Central PMCID: PMC2789838.
Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju Y-E, et al. Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system. Arch Neurol. 2012;69(1):51–8. Pubmed Central PMCID: PMC3254706.
Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bateman RJ, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of amyloid-β in mice with Alzheimer’s disease pathology. Sci Transl Med. 2012;4(15):150ra22. Pubmed Central PMCID: PMC3654377.
Dobrowolska JA, Kasten T, Huang Y, Benzinger TL, Sigurdson W, Ovod V, et al. Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system. PLoS One. 2014;9(3):e89998. Pubmed Central PMCID: PMC3960093.
Huang Y, Potter R, Sigurdson W, Kasten T, Connors R, Morris JC, et al. Beta-amyloid dynamics in human plasma. Arch Neurol. 2012;69(12):1591–7. Pubmed Central PMCID: PMC3808092.
Lucey BP, Gonzales C, Das U, Li J, Siemers ER, Slemmon JR, et al. An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter. Alzheimers Res Ther. 2015;7(1):53. Pubmed Central PMCID: PMC4518529.
Slats D, Claassen JA, Spies PE, Borm G, Besse KT, Aalst W, et al. Hourly variability of cerebrospinal fluid biomarkers in Alzheimer's disease subjects and healthy older volunteers. Neurobiol Aging. 2012;33(4):831.e1–9.
Lucey BP, Mawuenyega KG, Patterson BW, Elbert DL, Ovod V, Kasten T, et al. Associations Between β-Amyloid Kinetics and the β-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol. 2017;74(2):207–20.
Cicognola C, Chiasserini D, Eusebi P, Andreasson U, Vanderstichele H, Zetterberg H, et al. No diurnal variation of classical and candidate biomarkers of Alzheimer's disease in CSF. Mol Neurodegener. 2016;11(1):65. Pubmed Central PMCID: PMC5013624.
Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, et al. Amyloid-β dynamics correlate with neurological status in the injured human brain. Science. 2008;321(5893):1221–4.
Li J, Llano DA, Ellis T, LeBlond D, Bhathena A, Jhee SS, et al. Effect of human cerebrospinal fluid sampling frequency on amyloid-β levels. Alzheimers Dement. 2012;8(4):295–303.
Lucey BP, Fagan AM, Holtzman DM, Morris JC, Bateman RJ. Diurnal oscillation of CSF Aβ and other AD biomarkers. Mol Neurodeg. 2016. doi:10.1186/s13024-017-0161-4.
Cicognola C, Chiasserini D, Parnetti L. Preanalytical confounding factors in the analysis of cerebrospinal fluid biomarkers for Alzheimer's disease: the issue of diurnal variation. Front Neurol. 2015;6:143.
Olsson A, Csajbok L, Öst M, Höglund K, Nylén K, Rosengren L, Nellgård B, Blennow K. Marked increase of β-amyloid (1–42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury. J Neurol. 2004;251:870–6.
Bjerke M, Portelius E, Minthon L, Wallin A, Anckarsäter H, Anckarsäter R, Andreasen N, Zetterberg H, Andreasson U, Blennow K. Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid. Int J Alzheimers Dis. 2010. doi:10.4061/2010/986310.
Dr. Brendan Lucey’s is supported by a career development award funded by the National Institute on Aging (1K76AG054863-01). The funding source had no role in the writing of this manuscript.
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BPL drafted this commentary. AMF, DMH, JCM, and RJB revised and edited this commentary. CC drafted the Author’s response. DC, PE, UA, HV, HZ, LP and KB revised and edited the Author’s response. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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Lucey, B.P., Fagan, A.M., Holtzman, D.M. et al. Diurnal oscillation of CSF Aβ and other AD biomarkers. Mol Neurodegeneration 12, 36 (2017) doi:10.1186/s13024-017-0161-4
- Alzheimer’s disease