Cerebrospinal fluid levels of YKL-40 in prodromal Alzheimer’s disease

Wang, Lijun; Gao, Tianhao; Cai, Tengteng; Li, Kunyi; Zheng, Ping; Li, Jun; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1016/j.neulet.2019.134658

Cited by 25 publications

(18 citation statements)

References 40 publications

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“…CH3L1 is a glycoprotein hypothesized to modulate tissue remodeling, and is highly expressed in reactive astrocytes after both acute and chronic neuroinflammation [64-66]. Another recent study using ELISA assays also found increased CSF CH3L1 (YKL-40) levels in APOE4 carriers [67], further corroborating the findings presented here. Taken together, these findings strongly suggest that APOE4 carriers have increased neuroinflammation and astroglial activation [68-70] independent of their AD clinical status.…”

Section: Discussionsupporting

confidence: 89%

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

Berger

Cooter

Roesler

et al. 2020

Preprint

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Background: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objectives: To characterize CSF proteomic changes as a function of APOE4 copy number. Methods: We analyzed targeted proteomic data obtained on ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and a second linear model also adjusting for AD clinical status. False Discovery Rate (FDR) was used to correct for multiple comparisons. Results: In the first model, increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.006), and significant expression increases in peptides from ALDOA, CH3L1 (YKL-40), and FABPH (q<0.05 for each). In the second model (controlling for age, sex, and AD clinical status), increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.009). In both models, increased APOE4 copy number was associated with trends towards lower expression of all 24 peptides from all 8 different complement proteins measured here, although none of these differences were statistically significant. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusions: Increasing APOE4 copy number was associated with decreased CSF CRP levels and increased CSF ALDOA, CH3L1 and FABH levels; the CRP decrease remained significant after controlling for AD clinical status. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

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Section: Discussionsupporting

confidence: 89%

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

Berger

Cooter

Roesler

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Our finding of APOE4-related increases in CSF CH3L1 levels is corroborated by another recent study using ELISA assays that found increased CSF CH3L1 levels in APOE4 carriers [62], CH3L1 is a glycoprotein hypothesized to modulate tissue remodeling, and angiogenesis and is highly expressed in reactive astrocytes after acute and chronic neuroinflammation [63][64][65]. After traumatic brain injuries, CH3L1 knockout mice demonstrated greater astrogliosis, immune cell infiltration, and neurologic impairment compared to wild-type mice, suggesting CH3L1 plays a role in regulating neuroinflammation [66].…”

Section: Discussionsupporting

confidence: 90%

“…The decreased CSF CRP levels observed here may reflect CRP deposition in A␤ plaques and neurofibrillary tangles, in which CRP might play a role in promoting the development of AD. Low CSF CRP levels could also reflect increased CRP consumption from opsoninmediated glial phagocytosis in AD pathology, as previously suggested [62]. In this way, CSF CRP reductions might alternatively reflect a compensatory glial-dependent A␤ removal process in APOE4 carriers.…”

Section: Discussionmentioning

confidence: 54%

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1

Berger

Cooter

Roesler

et al. 2021

JAD

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Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

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“…Thus, increased expression of YKL-40 and protein levels in reactive astrocytes may be reflected in the CSF, indicating that astrocyte-associated metabolites may be utilized as potential biomarkers. Although data regarding elevated YKL-40 levels in CSF from early stages of AD are contradictory [16,17,[22][23][24]54], our results support the increase in YKL-40 levels in CSF from AD subjects, as well as the increased astrocytic YKL-40 levels associated with astrocytosis. Interestingly, we found that YKL-40 levels in CSF from PD patients were significantly lower compared with those levels in AD subjects suggesting that YKL-40, a marker of astroglial activation, is downregulated in PD.…”

Section: Discussionsupporting

confidence: 68%

Increased YKL-40 but Not C-Reactive Protein Levels in Patients with Alzheimer’s Disease

et al. 2021

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Neuroinflammation is a common feature in Alzheimer’s (AD) and Parkinson’s (PD) disease. In the last few decades, a testable hypothesis was proposed that protein-unfolding events might occur due to neuroinflammatory cascades involving alterations in the crosstalk between glial cells and neurons. Here, we tried to clarify the pattern of two of the most promising biomarkers of neuroinflammation in cerebrospinal fluid (CSF) in AD and PD. This study included cognitively unimpaired elderly patients, patients with mild cognitive impairment, patients with AD dementia, and patients with PD. CSF samples were analyzed for YKL-40 and C-reactive protein (CRP). We found that CSF YKL-40 levels were significantly increased only in dementia stages of AD. Additionally, increased YKL-40 levels were found in the cerebral orbitofrontal cortex from AD patients in agreement with augmented astrogliosis. Our study confirms that these biomarkers of neuroinflammation are differently detected in CSF from AD and PD patients.

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Cerebrospinal fluid levels of YKL-40 in prodromal Alzheimer’s disease

Cited by 25 publications

References 40 publications

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1

Increased YKL-40 but Not C-Reactive Protein Levels in Patients with Alzheimer’s Disease

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