The neuroinflammatory biomarker YKL-40 for neurodegenerative diseases: advances in development

ABSTRACT

Introduction: Neuroinflammation is a common pathophysiological mechanism in neurodegenerative diseases (ND). Cerebrospinal fluid (CSF) YKL-40 has recently been candidated as a neuroinflammatory biomarker of ND.

Areas covered: We provide an update on the role of CSF YKL-40 as a pathophysiological biomarker of ND. YKL-40 may discriminate Alzheimer’s disease (AD) from controls and may predict the progression from the early preclinical to the late dementia stage. In genetic AD, YKL-40 increases decades before the clinical onset. It does not seem a specific biomarker of a certain ND although sporadic Creutzfeldt–Jacob disease shows the highest YKL-40 concentrations. YKL-40 may discriminate between amyotrophic lateral sclerosis (ALS) and ALS-mimics. YKL-40 is potentially associated with the rate of ALS progression. YKL-40 correlates with biomarkers of neuronal injury, large axonal damage and synaptic disruption in various ND. It is not associated with the presence of the APOE-ε4 allele whereas possibly linked to aging, female sex, Hispanic ethnicity and some genetic variants of the chitinase-3-like 1 locus.

Expert opinion: There is growing evidence expanding the relevance of CSF YKL-40 as a pathophysiological biomarker for ND. Patients showing high YKL-40 levels might benefit from targeted clinical trials that use compounds acting against neuroinflammatory mechanisms, independently of the initial clinical diagnosis of ND.

KEYWORDS:

• YKL-40
• chitinase-3-like 1
• Alzheimer’s disease
• Amyotrophic lateral sclerosis
• Creutzfeldt-Jacob disease
• neurodegenerative diseases
• biomarkers
• cerebrospinal fluid biomarkers
• precision medicine

Article highlights

• CSF YKL-40 may discriminate hippocampal Alzheimer’s disease dementia from controls and predict the progression from the early preclinical to the late dementia stage.

• Sporadic Creutzfeldt–Jacob disease is characterized by the highest CSF YKL-40 concentrations.

• CSF YKL-40 contributes to distinguish amyotrophic lateral sclerosis (ALS) from controls and ALS mimics.

• CSF YKL-40 is associated with biomarkers of neuronal injury (total-tau, hyperphosphorylated-tau), large axonal damage (neurofilaments) and synaptic disruption (neurogranin) in neurodegenerative diseases.

• CSF YKL-40 is potentially related to the female sex, Hispanic ethnicity, and some genetic polymorphisms of the chitinase-3-like 1 gene. It is not associated with the APOE-ε4 allele.

• Patients with high CSF YKL-40 concentrations may benefit from targeted pharmacological trials against neuroinflammation, independently of the initial clinical diagnosis.

Declaration of interest

S. Lista received lecture honoraria from Roche. H. Hampel serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; he has received lecture fees from Biogen and Roche; research grants from Pfizer, Avid, and MSD Avenir (paid to his institution); travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics; consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation; and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics.

H. Hampel is also a co-inventor on the following patents as a scientific expert and has received no royalties:

• In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388

• In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784

• Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300

• In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463

• In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286

• In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822

• In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553

• CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797

• In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966

• Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by funding from the AXA Research fund, the ‘Fondation partenariale Sorbonne Université’ the ‘Fondation pour la Recherche sur Alzheimer’ and is a beneficiary of a grant from the French government ‘Investissements d’avenir’ number: ANR-10-IAIHU-06.