YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias |
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Authors: | Franc Llorens Katrin Thüne Waqas Tahir Eirini Kanata Daniela Diaz-Lucena Konstantinos Xanthopoulos Eleni Kovatsi Catharina Pleschka Paula Garcia-Esparcia Matthias Schmitz Duru Ozbay Susana Correia Ângela Correia Ira Milosevic Olivier Andréoletti Natalia Fernández-Borges Ina M. Vorberg Markus Glatzel Theodoros Sklaviadis Juan Maria Torres Susanne Krasemann Raquel Sánchez-Valle Isidro Ferrer Inga Zerr |
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Affiliation: | 1.Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED),Institute Carlos III, Ministry of Health, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat,Barcelona,Spain;2.Department of Neurology,University Medical School,G?ttingen,Germany;3.German Center for Neurodegenerative Diseases (DZNE),G?ttingen,Germany;4.Laboratory of Pharmacology, School of Health Sciences, Department of Pharmacy,Aristotle University of Thessaloniki,Thessaloniki,Greece;5.German Center for Neurodegenerative Diseases (DZNE),Bonn,Germany;6.Bellvitge University Hospital-IDIBELL, Department of Pathology and Experimental Therapeutics,University of Barcelona,Hospitalet de Llobregat,Spain;7.European Neuroscience Institute,G?ttingen,Germany;8.Institut National de la Recherche Agronomique/Ecole Nationale Vétérinaire,Toulouse,France;9.Centro de Investigación en Sanidad Animal (CISA-INIA),Madrid,Spain;10. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf,Hamburg,Germany;11.Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS),Barcelona,Spain;12.Present address: Unit of Lymphoid Malignancies, Division of Experimental Oncology,San Raffaele Scientific Institute,Milan,Italy |
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Abstract: | BackgroundYKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing.MethodsIn the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures.ResultsYKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer’s disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology.CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson’s disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations.ConclusionsOur results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component. |
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