Abstract

Purpose To determine if lamina cribrosa (LC) depth and curvature predict visual field (VF) progression rate in the African Descent and Glaucoma Evaluation Study (ADAGES) cohort in patients with primary open angle glaucoma (POAG).

Subjects Participants, and/or Controls. Three eyes from three research-consented brain-dead organ donors.

Methods Anterior laminar cribrosa surface depth (ALCSD) and LC curvature index (LCCI) were defined from 24 radial B-scan spectral domain optic coherence tomographic (SDOCT) images of each image. All scans were processed using a deep learning software to perform the segmentation and optic nerve health (ONH) layers. Univariable and multivariable linear mixed effects models were used to test associations between VF progression rate, ALCSD, and other demographic and clinical characteristics and known risk factors for progressive POAG. Additionally, the variable selection in the final multivariable model was reached using the Akaike information criterion index (AICc) and clinical utility.

Measures IOP change with exposure to NP.

Main Outcome The associations between ALCSD and LCCI with the rate of VF progression.

Results There was a statistically significant relationship between faster VF progression rates, and a deeper ALCSD (−0.02 dB/year/50 microns, p<0.001) and LCCI (−0.01unit/dB/year, p<0.001). There was also increasing progression seen in both models for with increasing age (−0.025dB/year/10 years, p<0.007), intraocular pressure (IOP) (−0.011dB/year per 2 mmHg, p=0.021), and disease severity (0.017dB/year per dB, p<0.001). The rate of progression was faster in the ED cohort (−0.056 dB/year, p=0.006) following propensity matching for disease severity and age.

Conclusions In the ADAGES cohort, there is a statistically significant association between VF progression rate and ALCSD and curvature (LCCI). A 50 um deeper LC at baseline had a similar effect of VF progression as being 10 years of age older. These data suggest that morphologic change in the ONH due to glaucomatous and age-related remodeling may induce greater vulnerability to develop progressive disease. Thus, LC depth and curvature may inform the likelihood and rate of glaucoma progression and are promising candidates for mechanistic biomarkers.

Competing Interest Statement

MAF: Financial support: National Institutes of Health; National Eye Institute; Centers for Disease Control; Research to Prevent Blindness; Heidelberg Engineering GmbH; Topcon Healthcare Inc. Non-financial support: Wolfram Research Inc. Royalties or licenses: Fast Prototyping Software Solutions LLC (founder). RNW: Consultant: Abbvie; Alcon; Amydis; Editas; Eyenovia; Iantrek; IOPtic; Implandata; iSTAR Medical; Nicox; Topcon Healthcare Inc. Non-financial support: Heidelberg Engineering GmbH; Konan Medical; Optovue; Centervue. Financial support: National Eye Institute; National Institute of Minority Health and Health Dispariies. Patents: Toromedes (co-founder); Carl Zeiss Meditec. JML: Financial support: Research to Prevent Blindness; Novartis. Consultant: Allergan; Genentech; Thea; Bausch & Lomb. LMZ: Consultant: AbbVie Inc.; Topcon Healthcare Inc. Financial support: National Institutes of Health; National Eye Institute; Carl Zeiss Meditec Inc.; Heidelberg Engineering GmbH; Optovue Inc.; Topcon Healthcare Inc.; Icare; Optomed. Patents: Zeiss Meditec; AISight Health (co-founder and board member). CAG: Financial support: National Institutes of Health; National Eye Institute; Centers for Disease Control; Research to Prevent Blindness. Non-financial support: Heidelberg Engineering GmbH; Topcon Healthcare Inc.

Funding Statement

Karla Murillo MPH has research funding from the 2023 Research to Prevent Blindness Medical Student Eye Research Fellowship. This work is supported by National Institute of Health (NIH) T35 EY033704 training grant, and NIH grants R01 EY026574, R01 EY027510, P30 EY022589; Unrestricted grant from Research to Prevent Blindness, NY. The funding organization had no role in the design or conduct of this research.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

ADAGES (registered at clinicaltrials.gov under NCT00221897) sites include the Hamilton Glaucoma Center at the Department of Ophthalmology, UCSD (data coordinating center), the Edward S. Harkness Eye Institute at Columbia University Irving Medical Center, and the Department of Ophthalmology and Visual Sciences at University of Alabama at Birmingham (UAB). All participants gave written informed consent. The institutional review boards at all three sites approved the study methods. All methods adhered to the tenets of the Declaration of Helsinki and to the Health Insurance Portability and Accountability Act.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

Financial Support Karla Murillo MPH has research funding from the 2023 Research to Prevent Blindness Medical Student Eye Research Fellowship.

This work is supported by National Institute of Health (NIH) T35 EY033704 training grant, and NIH grants R01 EY026574, R01 EY027510, P30 EY022589; Unrestricted grant from Research to Prevent Blindness, NY. The funding organization had no role in the design or conduct of this research.

Conflict of Interest MAF: Financial support: National Institutes of Health; National Eye Institute; Centers for Disease Control; Research to Prevent Blindness; Heidelberg Engineering GmbH; Topcon Healthcare Inc. Non-financial support: Wolfram Research Inc. Royalties or licenses: Fast Prototyping Software Solutions LLC (founder).

RNW: Consultant: Abbvie; Alcon; Amydis; Editas; Eyenovia; Iantrek; IOPtic; Implandata; iSTAR Medical; Nicox; Topcon Healthcare Inc. Non-financial support: Heidelberg Engineering GmbH; Konan Medical; Optovue; Centervue. Financial support: National Eye Institute; National Institute of Minority Health and Health Dispariies. Patents: Toromedes (co-founder); Carl Zeiss Meditec.

JML: Financial support: Research to Prevent Blindness; Novartis. Consultant: Allergan; Genentech; Thea; Bausch & Lomb. LMZ: Consultant: AbbVie Inc.; Topcon Healthcare Inc. Financial support: National Institutes of Health; National Eye Institute; Carl Zeiss Meditec Inc.; Heidelberg Engineering GmbH; Optovue Inc.; Topcon Healthcare Inc.; Icare; Optomed. Patents: Zeiss Meditec; AISight Health (co-founder and board member).

CAG: Financial support: National Institutes of Health; National Eye Institute; Centers for Disease Control; Research to Prevent Blindness. Non-financial support: Heidelberg Engineering GmbH; Topcon Healthcare Inc.

Data Availability

All data produced in the present study are available upon reasonable request to the authors

AbbreviationsADAfrican DescentADAGESAfrican Descent and Glaucoma Evaluation StudyAICcAkaike information criterion indexALCSDAnterior Lamina Cribrosa Surface DepthCTTCentral Corneal ThicknessDIGSDiagnostic Innovation and Glaucoma StudyDLDeep LearningEDEuropean DescentIOPIntraocular PressureLCLamina CribrosaLCCILaminar Cribrosa Curvature IndexONHOptic Nerve HeadPOAGPrimary Open Angle GlaucomaRGCRetinal ganglion cellsSDOCTSpectral Domain Optic Coherence TomographySITASwedish Interactive Thresholding AlgorithmVFVisual FieldVF MDVisual Field Mean DeviationUABUniversity of Alabama-BirminghamUCSDUniversity of California, San DiegoUSUnited States