Hourly variability of cerebrospinal fluid biomarkers in Alzheimer's disease subjects and healthy older volunteers

Abstract

Large hour-to-hour variability has previously been demonstrated in the cerebrospinal fluid (CSF) concentrations of Alzheimer's disease (AD) biomarkers amyloid β(42) (Aβ(42)) and Aβ(40) in healthy younger subjects. We investigated the within-subject variability over 36 hours in CSF Aβ and tau proteins, in older subjects and AD patients. Six patients with mild stage AD (59-85 years, Mini Mental State Examination (MMSE) 16-26) and 6 healthy older volunteers (64-77 years) received an intrathecal catheter from which, during 36 hours, each hour 6 mL of CSF was drawn. Concentrations of Aβ(42), Aβ(40), total tau, and phosphorylated tau were determined and the variability was analyzed. Within-subject variability within 3-hour periods was assessed as the coefficient of variation, which was comparable for these 4 biomarkers in controls (4.2%-4.6%) and AD (3.1%-5.8%). Variability over 12 hour periods was 5.3% to 9.5%. These findings suggest that CSF biomarker variability is relatively low in healthy older controls and AD patients. Furthermore, continuous sampling of CSF proved to be a useful and robust method, which may also be used to investigate AD pathogenesis and to evaluate pharmacotherapeutic interventions.

Hourly analysis of cerebrospinal fluid glucose shows large diurnal fluctuations

“…For a detailed description of the methods, we refer to a previous publication. 5 Glucose was measured with the hexokinase method, using a Cobas Mira analyzer. 3 …”

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…As a result, biomarkers or drugs are expected to be concentrated in the smaller volume of fluid of the old or with certain diseases. For example, Slats et al [160] sampled 6 ml of patients' CSF every hour for 36 h using indwelling L3-4 lumber puncture cannula. They noted total CSF protein and pathological tau increased over the study period in the Alzheimer's disease patients, but not in age-matched controls, suggesting an artefact in sampling from the frailer patients.…”

Pre-analytical and analytical factors influencing Alzheimer's disease cerebrospinal fluid biomarker variability

“…Most studies using enzyme-linked immunosorbent assays (ELISA) have not found any difference in CSF Aβ 42 and Tau levels after one freeze/thaw cycle [16,18,33,35,36], [Leitao submitted]. In contrast, one study found a significant loss of Aβ 42 after one single freeze/thaw cycle using a semi-quantitative method [37].…”

“…A diurnal variability was observed for Aβ peptides according to one study [40]. However, more recent studies were unable to replicate the finding that there is a temporal fluctuation in the CSF biomarker levels (Aβ, t-Tau and p-Tau) [16,41,42]. Therefore, there is no need to standardize a specific time interval during the day for CSF collection dedicated to AD biomarker assays.…”