title: Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer's disease in a memory clinic cohort.
abstract: BACKGROUND
  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.
  
  
  METHODS
  CSF 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.
  
  
  RESULTS
  Baseline 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).
  
  
  CONCLUSIONS
  CSF 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.
authors.affiliation: Alzheimer Center and Department of Neurology, VU University Medical Center, PO box 7057, 1007 MB, Amsterdam, The Netherlands. m.kester@vumc.nl.
authors.forename: Maartje I
authors.initials: MI
authors.lastname: Kester
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands. c.teunissen@vumc.nl.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Teunissen
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. sutphenc@neuro.wustl.edu.|Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. sutphenc@neuro.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. sutphenc@neuro.wustl.edu.
authors.forename: Courtney
authors.initials: C
authors.lastname: Sutphen
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. e.herries@wustl.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Herries
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. ladenson@wustl.edu.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Ladenson
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. chengjie@wubios.wustl.edu.|Division of Biostatistics, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. chengjie@wubios.wustl.edu.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.affiliation: Alzheimer Center and Department of Neurology, VU University Medical Center, PO box 7057, 1007 MB, Amsterdam, The Netherlands. p.scheltens@vumc.nl.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Alzheimer Center and Department of Neurology, VU University Medical Center, PO box 7057, 1007 MB, Amsterdam, The Netherlands. wm.vdflier@vumc.nl.|Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. wm.vdflier@vumc.nl.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. morrisj@abraxas.wustl.edu.|Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. morrisj@abraxas.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. morrisj@abraxas.wustl.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. holtzman@neuro.wustl.edu.|Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. holtzman@neuro.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. holtzman@neuro.wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. fagana@neuro.wustl.edu.|Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. fagana@neuro.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, 63110, MO, USA. fagana@neuro.wustl.edu.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
mesh_terms: D054392:Adipokines / Q000134:cerebrospinal fluid*; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D000704:Analysis of Variance; D015415:Biomarkers / Q000134:cerebrospinal fluid; D000071451:Chitinase-3-Like Protein 1; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D037102:Lectins / Q000134:cerebrospinal fluid*; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D051596:Neurocalcin / Q000134:cerebrospinal fluid*; D009483:Neuropsychological Tests; D016016:Proportional Hazards Models; D013129:Spinal Puncture
chemical_list: D054392:Adipokines; D015415:Biomarkers; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D051596:Neurocalcin; C496688:VSNL1 protein, human