Journal Article

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

Schmitz, Matthias, Tahir, Waqas, Sánchez-Valle, Raquel, Xanthopoulos, Konstantinos, Zerr, Inga, Kanata, Eirini, Kovatsi, Eleni, Pleschka, Catharina, Llorens, Franc, Ferrer, Isidro, Diaz-Lucena, Daniela, Garcia-Esparcia, Paula, Vorberg, Ina M., Ozbay, Duru, Milosevic, Ira, Thüne, Katrin, Sklaviadis, Theodoros, Glatzel, Markus, Torres, Juan Maria, Andréoletti, Olivier, Fernández-Borges, Natalia, Correia, Ângela, Krasemann, Susanne, Correia, Susana

2017

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alzheimer's disease / Arthritis / Astrocytes / Biomarkers / Biomedical and Life Sciences / Biomedicine / Brain / Brain research / Cancer / Cerebral cortex / Cerebrospinal fluid / Chitinase / Chitinase 3-like 1 / Creutzfeldt-Jakob disease / Dementia / Dementia disorders / Development and progression / Gene expression / Genetic aspects / Human health and pathology / Insomnia / Lewy bodies / Life Sciences / Microbiology and Parasitology / Molecular Medicine / Neurodegeneration / Neurodegenerative dementias / Neurodegenerative diseases / Neuroinflammation / Neurology / Neuropathology / Neurosciences / Pathogenesis / Physiological aspects / Research Article / Senile plaques / Sleep disorders / Stem cells / Stroke / Substantia alba / Vascular dementia / YKL-40 / β-Amyloid