Using Retinal diagnostics as a Biomarker for Neurodegenerative Diseases: Protocol for a systematic review

Introduction Retinal neurodegeneration has recently been shown to occur in tandem with neurodegenerative disease. In the expectation that disease modifying treatments for Alzheimer’s Disease and Parkinson’s Disease will soon become available, it will be important to have clinically useful biomarkers for neurodegenerative disease subtyping to guide early diagnosis, inform on prognosis and stratify subgroups for treatment. Understanding differences in detectable retina changes in individuals with different neurodegenerative disease subtypes is therefore fundamental. The emerging field of oculomics posits that systemic and neurodegenerative disease can be characterised using detectable ocular biomarkers within retinal diagnostics. The aim of this review is to compare the performance of common retinal imaging modalities in neurodegenerative disease detection and subtyping. Methods and analysis This protocol has been developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. A comprehensive literature search will be conducted in PubMed, Web of Science, and Scopus. Eligible studies will have reported using retinal diagnostic tools defined as Optical Coherence Tomography (OCT), Optical Coherence Tomography Angiography (OCTA), Colour Fundus Photography (CFP) and Electroretinography (ERG) in individuals with neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), Vascular Dementia (VaD), and Mild Cognitive Impairment (MCI). There will be no time restrictions placed in these searches. Studies not written in English, not peer-reviewed and grey literature will be excluded. Screening for eligible studies and data extraction will be conducted by two independent reviewers, using predefined inclusion criteria. Any disagreements between the reviewers will be settled by discussion, and if required, third senior reviewer arbitration. The systematic review primary outcome is the performance of retinal diagnostics, namely OCT, OCTA, CFP, and ERG in the detection and subtyping of aforementioned neurodegenerative diseases. The secondary outcome is to evaluate the association between changes in retinal diagnostic features (e.g. retinal layer thicknesses) and neurodegenerative disease subtypes. The quality of the included studies will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool. A narrative synthesis approach will be used to analyse the results, with meta-analysis performed if there is sufficient data. Ethics and Dissemination Ethical approval for this manuscript is not required, as this is a protocol for a systematic review and therefore no data are to be collected. Findings for this systematic review will be disseminated as a peer-reviewed publication and presentations at national and international symposiums including International Lewy body Dementia Conference, International Congress of Parkinson’s Disease and Movement Disorders, The Association for Research in Vision and Ophthalmology. PROSPERO Registration Number CRD42023434024 STRENGTHS AND LIMITATIONS OF THIS STUDY ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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 All data produced in the present work are contained in the manuscript