Sampling issues of cerebrospinal fluid and plasma monoamines: Investigation of the circadian rhythm and rostrocaudal concentration gradient

Jana Janssens,Sawal D Atmosoerodjo,Yannick Vermeiren,Anthony R Absalom,Izaak Den Daas,Peter P De Deyn

doi:10.1016/j.neuint.2019.04.015

Abstract

Biomarkers for neurodegenerative dementias offer interesting prospects regarding diagnosis and disease monitoring. Monoamines such as dopamine, (nor)adrenaline, serotonin (5-hydroxytryptamine or 5-HT), and their respective metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA), were shown to be altered in dementia, including Alzheimer's disease (AD). Biomarker research is hampered by potential confounds including the influence of time of day and volume of cerebrospinal fluid (CSF) collected. Therefore, the possibility of a circadian rhythm in CSF and plasma, and the presence of a rostrocaudal concentration gradient (RCG) in CSF for aforementioned monoamines/metabolites, were investigated.Circadian rhythmicity was assessed using reversed-phase ultra-high performance liquid chromatography with electrochemical detection (RP-UHPLC-ECD) to measure monoamine/metabolite concentrations in 271 paired CSF and plasma samples, successively collected over a period of 30 h and derived from eight healthy subjects. Plasma samples were also analyzed for melatonin, serving as positive control analyte, using ELISA. The RCG examination entailed RP-UHPLC-ECD analyses on five consecutive CSF samples derived from 10 patients with AD and 10 non-AD/control subjects.Besides a diurnal rhythm for melatonin, we found a similar rhythmicity for plasma HVA, with acrophases occurring between 02:00 and 06:00 h, in four out of seven subjects. Three and two subjects showed a circadian rhythm for CSF HVA and 5-HIAA, respectively. No rhythmicity was observed in any other compound. We found that only CSF MHPG, HVA and 5-HIAA levels differed across CSF fractions, and that these changes in 5-HIAA levels varied in the AD versus non-AD/control group. Positive correlations between CSF volume and HVA and 5-HIAA levels, indicative of a RCG, were also observed. Such a RCG could not be detected for the other monoamines/metabolites. Our results stress the importance of standardizing sampling procedures of biological fluids with respect to time of day, volume and number of samples.

Highlights

We found that only cerebrospinal fluid (CSF) MHPG, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels differed across CSF fractions, and that these changes in 5-HIAA levels varied in the Alzheimer's disease (AD) versus non-AD/control group
Our results indicated a 24-h rhythm in CSF 5-HIAA levels in two out of seven subjects, with acrophases ranging from 20:36–04:09 h (Fig. 2, panel D)
Despite relatively small study populations in this work, we found that plasma HVA levels vary according to a circadian rhythm similar to that of melatonin, which could be explained by a shared control mechanism in the suprachiasmatic nucleus (SCN)

Summary

Introduction

Amyloid beta peptide of 42 amino acids (Aβ1-42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-Tau181P) are widely known as the standard CSF biomarker panel to aid in the differential diagnosis of Alzheimer's disease (AD) (Dubois et al, 2014; Simonsen et al, 2017). Besides their application in diagnostic evaluation, biomarkers are implemented in other contexts of use, such as disease- and treatment response monitoring (Zverova, 2018). Some promising candidate molecules (plasma T-tau and serum neurofilament light chain) have already been identified (reviewed by Keshavan et al, 2017), but still face several challenges, among which are a lack of reproducibility (O'Bryant et al, 2017; Shi et al, 2018)

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Discussion

Conclusion