Neurofilament light chain in the vitreous humor of the eye

Manju L Subramanian,Steven Ness,Kaj Blennow,Madeleine Zetterberg,Farah Shareef,Gyungah R Jun,Weiming Xia,Viha Vig,Jaeyoon Chung,Marissa G Fiorello,Nicole H Siegel,Thor D Stein,Henrik Zetterberg

doi:10.1186/s13195-020-00677-4

Abstract

BackgroundNeurofilament light chain (NfL) is a promising biomarker of neurodegeneration in the cerebrospinal fluid and blood. This study investigated the presence of NfL in the vitreous humor and its associations with amyloid beta, tau, inflammatory cytokines and vascular proteins, apolipoprotein E (APOE) genotypes, Mini-Mental State Examination (MMSE) scores, systemic disease, and ophthalmic diseases.MethodsThis is a single-site, prospective, cross-sectional cohort study. Undiluted vitreous fluid (0.5–1.0 mL) was aspirated during vitrectomy, and whole blood was drawn for APOE genotyping. NfL, amyloid beta (Aβ), total Tau (t-Tau), phosphorylated Tau (p-Tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous were quantitatively measured by immunoassay. The main outcome measures were the detection of NfL levels in the vitreous humor and its associations with the aforementioned proteins. Linear regression was used to test the associations of NfL with other proteins, APOE genotypes, MMSE scores, and ophthalmic and systemic diseases after adjustment for age, sex, education level, and other eye diseases.ResultsNfL was detected in all 77 vitreous samples. NfL was not found to be associated with ophthalmic conditions, APOE genotypes, MMSE scores, or systemic disease (p > 0.05). NfL levels were positively associated with increased vitreous levels of Aβ40 (p = 7.7 × 10−5), Aβ42 (p = 2.8 × 10−4), and t-tau (p = 5.5 × 10−7), but not with p-tau181 (p = 0.53). NfL also had significant associations with inflammatory cytokines such as interleukin-15 (IL-15, p = 5.3 × 10−4), IL-16 (p = 2.2 × 10−4), monocyte chemoattractant protein-1 (MCP1, p = 4.1 × 10−4), and vascular proteins such as vascular endothelial growth factor receptor-1 (VEGFR1, p = 2.9 × 10−6), Vegf-C (p = 8.6 × 10−6), vascular cell adhesion molecule-1 (VCAM-1, p = 5.0 × 10−4), Tie-2 (p = 6.3 × 10−4), and intracellular adhesion molecular-1 (ICAM-1, p = 1.6 × 10−4).ConclusionNfL is detectable in the vitreous humor of the eye and significantly associated with amyloid beta, t-tau, and select inflammatory and vascular proteins in the vitreous. Additionally, NfL was not associated with patients’ clinical eye condition. Our results serve as a foundation for further investigation of NfL in the ocular fluids to inform us about the potential utility of its presence in the eye.

Highlights

Neurofilament light chain (NfL) is a promising biomarker of neurodegeneration in the cerebrospinal fluid and blood
The ethnic breakdown of our sample population is a close representation of the patient population typically seen at the eye clinic at Boston University Medical Center (BUMC), and 69% of the sample population were over the age of 50 years (Table 1)
After the NfL values were transformed via quality control and log2 transformation, NfL proteins were found to have a normal distribution in the vitreous humor (Fig. 1)

Summary

Introduction

Neurofilament light chain (NfL) is a promising biomarker of neurodegeneration in the cerebrospinal fluid and blood. Neurofilament light chain (NfL), a promising biomarker of neurodegeneration, has been identified in the cerebrospinal fluid (CSF) and blood as a potential screening tool and prognostic indicator, and it may be on the brink of clinical applicability [3]. Higher levels of NfL are seen in both the cerebrospinal fluid (CSF) and blood in those with neurodegenerative, inflammatory, or vascular injury of neurons, in several different neurological diseases, including multiple sclerosis (MS), AD, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), atypical Parkinsonian disorders (APDs), and traumatic brain injury (TBI). In addition to other biomarkers such as amyloid beta (Aβ) and tau protein, elevated levels of NfL in both the CSF and blood have been shown to differentiate healthy controls from subjects with AD with reliable accuracy [3, 5,6,7,8,9]. NfL is not yet being used as a screening tool in the clinical setting, the ability of serum NfL to detect and differentiate people suffering from neurodegenerative diseases from healthy controls has made it an important research subject in the last few decades [10]

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