YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer's Disease

Abstract

Background Disease-modifying therapies for Alzheimer’s disease (AD) would be most beneficial if applied during the ‘preclinical’ stage (pathology present with cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. Methods 2D–difference gel electrophoresis and liquid chromatography tandem mass spectrometry were used to measure AD-associated changes in cerebrospinal fluid (CSF). Concentrations of CSF YKL-40 were further evaluated by enzyme-linked immunosorbent assay in the discovery cohort (N=47), an independent sample set (N=292) with paired plasma samples (N=237), frontotemporal lobar degeneration (N=9), and progressive supranuclear palsy (PSP, N=6). Human AD brain was studied immunohistochemically to identify potential source(s) of YKL-40. Results In the discovery and validation cohorts, mean CSF YKL-40 was higher in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) vs. controls (CDR 0) and PSP. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 vs. CDR 0 groups, and correlated with CSF levels. YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. Conclusions These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD, and that, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

“…In agreement with previous studies, CSF YKL40 was increased in FTLD and AD compared to controls 35, 36, 37. FTLD‐TDP had the highest YKL‐40 values, which were comparable to those observed in AD patients, but different to those observed in CON, FTLD‐Tau, or DLB.…”

Cerebrospinal fluid biomarkers of Alzheimer’s disease

“…The expression of YKL-40 in the CSF is elevated in early AD. The ratio of YKL-40 to Aβ42 predicts cognitive impairment as well as the best CSF biomarkers (Aβ42, t-tau, and p-tau) [83] , suggesting potential as a biomarker for preclinical AD. dementias, and that CSF VILIP-1/Aβ42 predicts cognitive impairment as well as tau/Aβ42 and p-tau181/Aβ42 [84,85] .…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…Furthermore, to simplify the clinical diagnosis, several peripheral biomarkers have already been chosen as supportive indicators, including the level of Aβ1‐42 and p‐tau181 within the CSF (cerebrospinal fluid) and the rate of glucose uptake by FDG‐PET (fluorodeoxyglucose‐positron emission tomography) (Ballard, Gauthier, Corbett, Brayne, & Aarsland, 2011; Cohen & Klunk, 2017; Khan & Alkon, 2015; Lista, Garaci, Ewers, Teipel, & Zetterberg, 2014). Moreover, other biomarkers are believed to have potential diagnostic values based on preliminary analyses, including ApoE4 level in the blood, YKL‐40 (chitinase‐3 like‐1) level in the CSF, and NTP (neuronal thread protein) level in the urine, despite insufficient confirmatory evidence (Craig‐Schapiro, Perrin, Roe, Xiong, & Carter, 2010; Farrer, 1997; Lonneborg, 2008). The combination of these diagnostic biomarkers could largely increase the accuracy and potential early diagnosis and thus benefit the prognosis of patients (Table 1).…”