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. 2020 Sep 17;12(1):111.
doi: 10.1186/s13195-020-00677-4.

Neurofilament light chain in the vitreous humor of the eye

Manju L Subramanian  1 , Viha Vig  2 , Jaeyoon Chung  3 , Marissa G Fiorello  2 , Weiming Xia  4   5 , Henrik Zetterberg  6   7   8   9 , Kaj Blennow  6   7 , Madeleine Zetterberg  10 , Farah Shareef  11 , Nicole H Siegel  2 , Steven Ness  2 , Gyungah R Jun  3 , Thor D Stein  12   13   14
Affiliations

Neurofilament light chain in the vitreous humor of the eye

Manju L Subramanian et al. Alzheimers Res Ther. .

Abstract

Background: Neurofilament 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.

Methods: This 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.

Results: NfL 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).

Conclusion: NfL 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.

Keywords: Alzheimer’s disease; Amyloid beta; Neuro-filament light chain; Ocular biomarkers; Tau; Vitreous humor.

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Conflict of interest statement

Henrik Zetterberg (HZ) has served at the scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Kaj Blennow has served as a consultant at the advisory boards or at the data monitoring committees for Abcam, Axon, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. The other authors have no conflict of interest to report.

Figures

Fig. 1
Fig. 1
Normal distribution of NfL. Distribution of neurofilament light chain levels in the vitreous humor after log2 transformation
Fig. 2
Fig. 2
a–c Regression plots for NfL’s association with AD biomarkers. Higher levels of NfL (n = 77) are significantly correlated with higher levels of Aβ40 (a) p = 7.7 × 10−5, Aβ42 (b) p = 2.8 × 10−4, and t-tau (c) p = 5.5 × 10−7. p values were computed from linear regression models after adjusting for diabetes
Fig. 3
Fig. 3
Boxplot of NfL with APOE genotype obtained from the subjects’ blood. No significant association is observed between APOE alleles 23, 23, 33, and 34, with vitreous NfL levels
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