Longitudinal Stability of Cerebrospinal Fluid Biomarker Levels: Fulfilled Requirement for Pharmacodynamic Markers in Alzheimer's Disease

Article type: Research Article

Authors: Le Bastard, Nathalie^{a; *} | Aerts, Laetitia^{b; 2} | Sleegers, Kristel^{c; d} | Martin, Jean-Jacques^b | Van Broeckhoven, Christine^c | De Deyn, Peter Paul^{a; b; e; f; 1} | Engelborghs, Sebastiaan^{a; e; 1}

Affiliations: [a] Laboratory of Neurochemistry and Behavior, Reference Center for Biological Markers of Dementia (BIODEM), Antwerp, Belgium | [b] Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium | [c] Neurodegenerative Brain Disease Group, Department of Molecular Genetics, VIB, Antwerp, Belgium | [d] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium | [e] Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium | [f] Department of Neurology and Alzheimer Research Center, University Medical Center Groningen (UMCG), Groningen, The Netherlands

Correspondence: [*] Correspondence to: Dr. Nathalie Le Bastard, Laboratory of Neurochemistry and Behavior, Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium. Tel.: +32 3 265 26 31; Fax: +32 3 265 26 18; E-mail: [email protected].

Note: [1] Joint last authors.

Note: [2] Current affiliation: Faculté de Médecine, Centre de Recherche en Infectiologie du Centre Hospitalier de l'Université Laval, Université Laval, Québec, Canada.

Abstract: The current treatment for Alzheimer's disease (AD) is purely symptomatic, but medications interfering with underlying pathophysiological processes are being developed. To evaluate a possible disease-modifying effect, cerebrospinal fluid (CSF) biomarkers with a direct link to the underlying pathophysiology, such as amyloid-β1-42 (Aβ1-42), total tau protein (T-tau), and hyperphosphorylated tau (P-tau181P), may play an important role. If intra-individual fluctuations in biomarker levels are small, the difference between two samples could serve as a pharmacodynamic measure. The aim of this study was to evaluate the longitudinal stability of CSF Aβ1-42, T-tau, and P-tau181P levels in AD patients and control subjects. Serial CSF samples of 28 AD patients and 23 controls with a minimum time interval of 30 days were included in this study. Serial CSF samples from 10 progressive patients (7 mild cognitive impairment (MCI) patients and 3 controls progressing to MCI or AD) were also analyzed. Intra-individual CSF Aβ1-42 and P-tau181P levels were stable in AD and controls. Intra-individual CSF T-tau levels differed significantly in AD patients, but not in controls. Change in biomarker concentrations per time unit was also significant between groups, but not within groups. The difference in biomarker levels in samples from progressive patients was not significant. In conclusion, CSF levels of Aβ1-42, T-tau, and P-tau181P are relatively stable over time. Only T-tau increased in AD patients in comparison to controls, which does not preclude its use as a diagnostic marker, nor as a potential pharmacodynamic marker.

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, intra-individual variation, longitudinal sampling

DOI: 10.3233/JAD-2012-110029

Journal: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 807-822, 2013