Using Retinal diagnostics as a Biomarker for Neurodegenerative Diseases: Protocol for a systematic review
Authors: Sahin Zeynep , Pisani Sara , Nderitu Paul , Venkataraman Ashwin V , Guu Ta-Wei , Aarsland Dag , Jackson Timothy , ffytche Dominic 
Published: May 2024

ABSTRACTIntroductionRetinal 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 analysisThis protocol has been developed in accordance with thePreferred 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 Studies not written in English, not peer-reviewed and grey literature will be excluded.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 DisseminationEthical 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 NumberCRD42023434024STRENGTHS AND LIMITATIONS OF THIS STUDY▪Our aim is to perform a comprehensive systematic review of the performance of retinal diagnostic methods, namely OCT, OCTA, CFP, and ERG in neurodegenerative disease subtyping.▪We will use the carefully defined methodology in accordance with the Cochrane handbook, and the results of this systematic review will be reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) statement.▪The certainty of this systematic review may be limited due to the small sample of studies for Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VaD).