YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias

• Main 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
• Format: Article
• Language: English
• Published: BMC 2017-11-01
• Series: Molecular Neurodegeneration
• Subjects: Chitinase 3-like 1; YKL-40; Neuroinflammation; Cerebrospinal fluid; Neurodegenerative dementias; Brain
• Online Access: http://link.springer.com/article/10.1186/s13024-017-0226-4

Abstract Background YKL-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. Methods In 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. Results YKL-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. Conclusions Our 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.