Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer's disease in a memory clinic cohort.

Maartje I Kester,Anne M Fagan,David M Holtzman,Jack H Ladenson,Philip Scheltens,Elizabeth M Herries,Chengjie Xiong,Charlotte E Teunissen,Wiesje M Van Der Flier,John C Morris,Courtney Sutphen

doi:10.1186/s13195-015-0142-1

Abstract

IntroductionWe examined the utility of cerebrospinal fluid (CSF) proteins, Chitinase-3-like protein 1 (CHI3L1 or YKL-40), a putative marker of inflammation, and Visinin-like protein-1 (VILIP-1), a marker for neuronal injury, for diagnostic classification and monitoring of disease progression in a memory clinic cohort.MethodsCSF levels of YKL-40 and VILIP-1 were measured in 37 cognitively normal, 61 Mild Cognitive Impairment (MCI) and 65 Alzheimer’s disease (AD) patients from the memory clinic-based Amsterdam Dementia Cohort who underwent two lumbar punctures, with minimum interval of 6 months and a mean(SE) interval of 2.0(0.1) years. Mean(SE) cognitive follow-up was 3.8 (0.2) years. ANOVA was used to compare baseline differences of log-transformed CSF measures. Cox proportional hazard models were used to evaluate disease progression as a function of CSF tertiles. Linear mixed models were used to evaluate longitudinal change over time. All analyses were sex and age adjusted.ResultsBaseline levels of YKL-40, but not VILIP-1, were higher in MCI and AD patients compared to cognitively normal individuals (mean (SE) pg/mL, 304 (16) and 288 (12) vs. 231 (16), p = 0.03 and p = 0.006). Baseline levels of both YKL-40 and VILIP-1 in MCI predicted progression to AD (HR 95 % CI = 3.0 (1.1–7.9) and 4.4 (1.5–13.0), respectively, for highest vs. lowest tertile). YKL-40 increased longitudinally in patients with MCI and AD (mean (SE) pg/mL per year, 8.9 (3.0) and 7.1 (3.1), respectively), but not in cognitively normal individuals, whereas levels of VILIP-1 increased only in MCI (mean (SE), 10.7 (2.6) pg/mL per year).ConclusionsCSF levels of YKL-40 may have utility for discriminating between cognitively normal individuals and patients with MCI or AD. Increased levels of both YKL-40 and VILIP-1 may be associated with disease progression. These CSF biomarkers should be considered for future evaluation in the characterization of the natural history of AD.

Highlights

We examined the utility of cerebrospinal fluid (CSF) proteins, Chitinase-3-like protein 1 (CHI3L1 or YKL-40), a putative marker of inflammation, and Visinin-like protein-1 (VILIP-1), a marker for neuronal injury, for diagnostic classification and monitoring of disease progression in a memory clinic cohort
The reported β value represents the estimated change of YKL-40 or VILIP-1 levels per year aBaseline MMSE was available for 52 patients *p ≤0.05 vs. sMCI **p ≤0.005 vs. sMCI ‡p ≤0.005 for time effect §p ≤0.05 for time effect Amyloid beta 1–42 (Aβ42) amyloid beta 1–42, ANOVA analysis of variance, CSF cerebrospinal fluid, LP lumbar puncture, MCI-AD mild cognitive impairment progressing to Alzheimer’s disease, MMSE Mini-Mental State Examination, ptau-181 tau phosphorylated at threonine 181, sMCI stable mild cognitive impairment, Standard error (SE) standard error, tau total tau, VILIP-1 Visinin-like protein-1, YKL-40 Chitinase-3-like protein 1
We show that levels of YKL-40 increased over time in both MCI and AD, and that levels of VILIP-1 increased over time in MCI, indicating that both of these CSF biomarkers might be useful for disease monitoring

Summary

Introduction

We examined the utility of cerebrospinal fluid (CSF) proteins, Chitinase-3-like protein 1 (CHI3L1 or YKL-40), a putative marker of inflammation, and Visinin-like protein-1 (VILIP-1), a marker for neuronal injury, for diagnostic classification and monitoring of disease progression in a memory clinic cohort. (ptau-181) reflect the neuropathology of AD and are useful as diagnostic markers for AD [5] These “classical CSF biomarkers” predict progression to AD in cognitively normal individuals and individuals with mild cognitive impairment (MCI) [16, 18, 23, 47]. Several studies have evaluated whether these classical CSF biomarkers could be used as markers to monitor progression of AD pathology in affected individuals but, to date, their levels have not been shown to be optimal markers for (therapeutic) monitoring in longitudinal studies owing to their relative stability in the later clinical stages of AD [6, 10, 14, 22, 33, 44, 48].

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