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

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.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0226-4) contains supplementary material, which is available to authorized users.

Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease

“…Although several studies revealed an increase in CSF CHI3L1 levels, which correlated with CSF markers for tau and amyloid in AD [75,76], we did not find a correlation between CHI3L1 levels/counts and neuritic and diffuse plaques or NFTs. Similar to that in other reports [77], we observed CHI3L1-positive astrocytes in close apposition to amyloid plaques in MCI and AD. However, many CHI3L1-ir astrocytes were independent of plaque pathology, suggesting that amyloid is not a necessary precondition for the onset of CHI3L1 expression in Fig.…”

Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease

“…YKL-40, a disease-specific marker of neuro-inflammation expressed in astrocytes, displayed the lowest sensitivity (76.2%) among CSF biomarkers herein tested. Elevated CSF YKL-40 levels are reported in sCJD, gCJD associated with E200K, and V210I mutations, and, to a lesser extent, in fatal familial insomnia [28]. CSF YKL-40 also appeared to be increased in other neurodegenerative dementias such as AD and FTD, but not in DLB [28,52,53].…”

“…Nfl (n = 21) displayed a sensitivity of 85.7% using a cut-off of 7000 pg/mL [27] with a mean concentration of 12,986 pg/mL. The mean YKL-40 concentration (n = 21) was 441 ng/mL with a sensitivity of 76.2% based on a sCJD cut-off of 315 ng/mL [28]. Finally, RT-QuIC positive reactions were detected in 18 out of 21 cases (sensitivity of 85.7%) based on a cut-off of 10,000 relative fluorescent units (RFU) for sCJD [20]; mean RFU was 41,129 ( Table 3).…”

Proteomics of neurodegenerative diseases: analysis of human post‐mortem brain

“…), and may reflect the abnormality of astrocyte activity associated with inflammatory processes (Llorens et al . ).…”