Retinal imaging as a source of biomarkers for diagnosis, characterization and prognosis of chronic illness or long-term conditions.

The black void behind the pupil was optically impenetrable before the invention of the ophthalmoscope by von Helmholtz over 150 years ago. Advances in retinal imaging and image processing, especially over the past decade, have opened a route to another unexplored landscape, the retinal neurovascular architecture and the retinal ganglion pathways linking to the central nervous system beyond. Exploiting these research opportunities requires multidisciplinary teams to explore the interface sitting at the border between ophthalmology, neurology and computing science. It is from the detail and depth of retinal phenotyping that novel metrics and candidate biomarkers are likely to emerge. Confirmation that in vivo retinal neurovascular measures are predictive of microvascular change in the brain and other organs is likely to be a major area of research activity over the next decade. Unlocking this hidden potential within the retina requires integration of structural and functional data sets, that is, multimodal mapping and longitudinal studies spanning the natural history of the disease process. And with further advances in imaging, it is likely that this area of retinal research will remain active and clinically relevant for many years to come. Accordingly, this review looks at state-of-the-art retinal imaging and its application to diagnosis, characterization and prognosis of chronic illness or long-term conditions.

[1]  D L DeMets,et al.  The Wisconsin epidemiologic study of diabetic retinopathy. XI. The incidence of macular edema. , 1989, Ophthalmology.

[2]  B. Wasan,et al.  Vascular network changes in the retina with age and hypertension , 1995, Journal of hypertension.

[3]  Hiroshi Fujita,et al.  Automated segmentation of optic disc region on retinal fundus photographs: Comparison of contour modeling and pixel classification methods , 2011, Comput. Methods Programs Biomed..

[4]  R. Klein,et al.  Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study. , 2002, JAMA.

[5]  Enrico Grisan,et al.  Detection of optic disc in retinal images by means of a geometrical model of vessel structure , 2004, IEEE Transactions on Medical Imaging.

[6]  Amy Conger,et al.  Retinal Nerve Fiber Layer Thickness in Multiple Sclerosis , 2011, Türk Oftalmoloji Dergisi.

[7]  Kenneth W. Tobin,et al.  Exudate-based diabetic macular edema detection in fundus images using publicly available datasets , 2012, Medical Image Anal..

[8]  Ronald Klein,et al.  Changes in retinal vessel diameter and incidence and progression of diabetic retinopathy. , 2012, Archives of ophthalmology.

[9]  Tien Yin Wong,et al.  Is retinal photography useful in the measurement of stroke risk? , 2004, The Lancet Neurology.

[10]  Gavin Robertson,et al.  Investigating post-processing of scanning laser ophthalmoscope images for unsupervised retinal blood vessel detection , 2013, Proceedings of the 26th IEEE International Symposium on Computer-Based Medical Systems.

[11]  A. Stanton,et al.  A method of quantifying retinal microvascular alterations associated with blood pressure and age , 1995, Journal of hypertension.

[12]  Hiroshi Fujita,et al.  Determination of cup-to-disc ratio of optical nerve head for diagnosis of glaucoma on stereo retinal fundus image pairs , 2009, Medical Imaging.

[13]  Milan Sonka,et al.  Vessel segmentation in 3D spectral OCT scans of the retina , 2008, SPIE Medical Imaging.

[14]  D L DeMets,et al.  The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. , 1989, Archives of ophthalmology.

[15]  J. Liu,et al.  Level-set based automatic cup-to-disc ratio determination using retinal fundus images in ARGALI , 2008, 2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[16]  J. J. Wang,et al.  Retinal vascular tortuosity in persons with diabetes and diabetic retinopathy , 2011, Diabetologia.

[17]  Ying Sun,et al.  Back-propagation network and its configuration for blood vessel detection in angiograms , 1995, IEEE Trans. Neural Networks.

[18]  Stephen J. McKenna,et al.  RERBEE: Robust Efficient Registration via Bifurcations and Elongated Elements Applied to Retinal Fluorescein Angiogram Sequences , 2012, IEEE Transactions on Medical Imaging.

[19]  Jie-Jin Wang,et al.  Update: Systemic diseases and the cardiovascular system (V) Retinal Vascular Signs: A Window to the Heart? , 2017 .

[20]  Jie-Jin Wang,et al.  Update: Systemic diseases and the cardiovascular system (V) Retinal Vascular Signs: A Window to the Heart? , 2017 .

[21]  T. Sano,et al.  [Diabetic retinopathy]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[22]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[23]  Gary R Cutter,et al.  Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. , 2006, Ophthalmology.

[24]  Bram van Ginneken,et al.  Automated Measurement of the Arteriolar-to-Venular Width Ratio in Digital Color Fundus Photographs , 2011, IEEE Transactions on Medical Imaging.

[25]  Barbara E K Klein,et al.  Relation of retinopathy to coronary artery calcification: the multi-ethnic study of atherosclerosis. , 2007, American journal of epidemiology.

[26]  J Martin,et al.  Effect of optic neuritis on progressive axonal damage in multiple sclerosis patients , 2011, Multiple sclerosis.

[27]  Dinesh Kumar,et al.  Validating retinal fundus image analysis algorithms: issues and a proposal. , 2013, Investigative ophthalmology & visual science.

[28]  Kim L. Boyer,et al.  Retinal thickness measurements from optical coherence tomography using a Markov boundary model , 2001, IEEE Transactions on Medical Imaging.

[29]  P. Calabresi,et al.  Retinal Ganglion Cell Layer Volumetric Assessment by Spectral-Domain Optical Coherence Tomography in Multiple Sclerosis: Application of a High-Precision Manual Estimation Technique , 2011, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[30]  A. Hofman,et al.  Determinants of disease and disability in the elderly: The Rotterdam elderly study , 1991, European Journal of Epidemiology.

[31]  J. J. Wang,et al.  Retinal vascular calibre and the risk of coronary heart disease-related death , 2006, Heart.

[32]  R. Klein,et al.  Relationship Between Retinal Arteriolar Narrowing and Myocardial Perfusion: Multi-Ethnic Study of Atherosclerosis , 2008, Hypertension.

[33]  C. Rowe,et al.  Retinal vascular biomarkers for early detection and monitoring of Alzheimer's disease , 2013, Translational Psychiatry.

[34]  R. Klein,et al.  Retinal arteriolar narrowing and left ventricular remodeling: the multi-ethnic study of atherosclerosis. , 2007, Journal of the American College of Cardiology.

[35]  Charles V. Stewart,et al.  Retinal Vessel Centerline Extraction Using Multiscale Matched Filters, Confidence and Edge Measures , 2006, IEEE Transactions on Medical Imaging.

[36]  Young H. Kwon,et al.  Automated segmentation of the optic disc from stereo color photographs using physiologically plausible features. , 2007, Investigative ophthalmology & visual science.

[37]  B. van Ginneken,et al.  Automated detection and differentiation of drusen, exudates, and cotton-wool spots in digital color fundus photographs for diabetic retinopathy diagnosis. , 2007, Investigative ophthalmology & visual science.

[38]  Joshua R. Ehrlich,et al.  Detection of retinal changes in Parkinson’s disease with spectral-domain optical coherence tomography , 2010, Clinical ophthalmology.

[39]  J. Singh,et al.  Hypertensive retinopathy. , 1983, Indian journal of ophthalmology.

[40]  P. Romano Association for Research in Vision and Ophthalmology. , 2000, Binocular vision & strabismus quarterly.

[41]  J. Nawrocki,et al.  Selmaj Optical coherence tomography in multiple sclerosis Thickness of the retinal nerve fiber layer as a potential measure of axonal loss and brain atrophy , 2022 .

[42]  Ole Vilhelm Larsen,et al.  Screening for diabetic retinopathy using computer based image analysis and statistical classification , 2000, Comput. Methods Programs Biomed..

[43]  Giovanni Gregori,et al.  Registration of OCT fundus images with color fundus photographs based on blood vessel ridges , 2010, Optics express.

[44]  Anthony J. Yezzi,et al.  Vessel Segmentation Using a Shape Driven Flow , 2004, MICCAI.

[45]  Charles V. Stewart,et al.  A Feature-Based, Robust, Hierarchical Algorithm for Registering Pairs of Images of the Curved Human Retina , 2002, IEEE Trans. Pattern Anal. Mach. Intell..

[46]  J. Sepulcre,et al.  Retinal nerve fiber layer atrophy is associated with physical and cognitive disability in multiple sclerosis , 2008, Multiple sclerosis.

[47]  Pablo Villoslada,et al.  Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS , 2007, Neurology.

[48]  L. Pablo,et al.  Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients , 2011, British Journal of Ophthalmology.

[49]  Paul Mitchell,et al.  The eye in hypertension , 2007, The Lancet.

[50]  Ž. Reiner,et al.  Relation of atherosclerotic changes in retinal arteries to the extent of coronary artery disease. , 2005, The American journal of cardiology.

[51]  R. Gross Retinal vascular caliber and risk of dementia , 2011 .

[52]  M. Sonka,et al.  Retinal Imaging and Image Analysis. , 2010, IEEE transactions on medical imaging.

[53]  T. MacGillivray,et al.  Differences in retinal vessels support a distinct vasculopathy causing lacunar stroke , 2009, Neurology.

[54]  Neil M Bressler,et al.  Retinal arteriolar narrowing and risk of coronary heart disease. , 2003, Archives of ophthalmology.

[55]  Andrea Giachetti,et al.  The use of radial symmetry to localize retinal landmarks , 2013, Comput. Medical Imaging Graph..

[56]  R. Kronmal,et al.  Multi-Ethnic Study of Atherosclerosis: objectives and design. , 2002, American journal of epidemiology.

[57]  Gerald Liew,et al.  Manifestaciones vasculares retinianas: ¿reflejan el estado del corazón? , 2011 .

[58]  S. A. Meyer,et al.  Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness , 2011, Multiple sclerosis.

[59]  Tien Yin Wong,et al.  Retinal arteriolar tortuosity is associated with retinopathy and early kidney dysfunction in type 1 diabetes. , 2012, American journal of ophthalmology.

[60]  P. Mitchell,et al.  Retinal Vascular Imaging: A New Tool in Microvascular Disease Research , 2008, Circulation. Cardiovascular imaging.

[61]  Tien Yin Wong,et al.  Fractal analysis of retinal microvasculature and coronary heart disease mortality. , 2011, European heart journal.

[62]  Tom MacGillivray,et al.  The association between retinal vascular network geometry and cognitive ability in an elderly population. , 2007, Investigative ophthalmology & visual science.

[63]  Milan Sonka,et al.  Three-Dimensional Analysis of Retinal Layer Texture: Identification of Fluid-Filled Regions in SD-OCT of the Macula , 2010, IEEE Transactions on Medical Imaging.

[64]  Elliot M. Frohman,et al.  Optical coherence tomography as a potential readout in clinical trials , 2010, Therapeutic advances in neurological disorders.

[65]  Ying Sun,et al.  Recursive tracking of vascular networks in angiograms based on the detection-deletion scheme , 1993, IEEE Trans. Medical Imaging.

[66]  Pascale Massin,et al.  A contribution of image processing to the diagnosis of diabetic retinopathy-detection of exudates in color fundus images of the human retina , 2002, IEEE Transactions on Medical Imaging.

[67]  Andrea Giachetti,et al.  Effective features for artery-vein classification in digital fundus images , 2012, 2012 25th IEEE International Symposium on Computer-Based Medical Systems (CBMS).

[68]  M. Ramanathan,et al.  Retinal nerve fiber layer thickness is associated with brain MRI outcomes in multiple sclerosis , 2008, Journal of the Neurological Sciences.

[69]  Albert Hofman,et al.  Retinal Vessel Diameters and Risk of Hypertension The Rotterdam Study , 2006 .

[70]  R. Klein,et al.  Cerebral white matter lesions, retinopathy, and incident clinical stroke. , 2002, JAMA.

[71]  M. Goldbaum,et al.  Detection of blood vessels in retinal images using two-dimensional matched filters. , 1989, IEEE transactions on medical imaging.

[72]  R. Klein,et al.  Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA). , 2006, Investigative ophthalmology & visual science.

[73]  Dan Liu,et al.  Image-based Blood Flow Simulation in the Retinal Circulation , 2009 .

[74]  J. Wardlaw,et al.  Retinal microvascular abnormalities and stroke: a systematic review , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[75]  G. Quellec,et al.  Automated assessment of diabetic retinopathy severity using content-based image retrieval in multimodal fundus photographs. , 2011, Investigative ophthalmology & visual science.

[76]  Qin Li,et al.  Retinopathy Online Challenge: Automatic Detection of Microaneurysms in Digital Color Fundus Photographs , 2010, IEEE Transactions on Medical Imaging.

[77]  Haizhou Li,et al.  ARGALI: An Automatic Cup-to-Disc Ratio Measurement System for Glaucoma Analysis Using Level-set Image Processing , 2009 .

[78]  Chia-Ling Tsai,et al.  The dual-bootstrap iterative closest point algorithm with application to retinal image registration , 2003, IEEE Transactions on Medical Imaging.

[79]  M. Schwartz,et al.  The retina as a window to the brain—from eye research to CNS disorders , 2013, Nature Reviews Neurology.

[80]  L. Pablo,et al.  Progressive degeneration of the retinal nerve fiber layer in patients with multiple sclerosis. , 2012, Investigative ophthalmology & visual science.

[81]  P. Sandercock,et al.  Is Breakdown of the Blood-Brain Barrier Responsible for Lacunar Stroke, Leukoaraiosis, and Dementia? , 2003, Stroke.

[82]  R. Klein,et al.  Retinal vascular tortuosity, blood pressure, and cardiovascular risk factors. , 2011, Ophthalmology.

[83]  Tien Yin Wong,et al.  A prospective cohort study of retinal arteriolar narrowing and mortality. , 2004, American journal of epidemiology.

[84]  N.M. Tan,et al.  Intelligent fusion of cup-to-disc ratio determination methods for glaucoma detection in ARGALI , 2009, 2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[85]  B. Amsterdam Retinal vessel diameters and risk of stroke:The Rotterdam Study , 2006 .

[86]  Peter F. Sharp,et al.  Automated microaneurysm detection , 1996, Proceedings of 3rd IEEE International Conference on Image Processing.

[87]  Roberto Marcondes Cesar Junior,et al.  Retinal vessel segmentation using the 2-D Gabor wavelet and supervised classification , 2005, IEEE Transactions on Medical Imaging.

[88]  Emanuele Trucco,et al.  Accurate estimation of retinal vessel width using bagged decision trees and an extended multiresolution Hermite model , 2013, Medical Image Anal..

[89]  J. Alvarez-Linera,et al.  Clinically Isolated Syndromes Suggestive of Multiple Sclerosis: An Optical Coherence Tomography Study , 2012, PloS one.

[90]  R. Agati,et al.  Leukoaraiosis and dementia. , 1990, Stroke.

[91]  T. Wong,et al.  Retinal Signs and Stroke: Revisiting the Link Between the Eye and Brain , 2008, Stroke.

[92]  R. Mayeux,et al.  Epidemiology of Alzheimer disease , 2011, Nature Reviews Neurology.

[93]  R. Klein,et al.  Retinal Microvascular Signs and Risk of Stroke: The Multi-Ethnic Study of Atherosclerosis (MESA) , 2012, Stroke.

[94]  Bunyarit Uyyanonvara,et al.  Blood vessel segmentation methodologies in retinal images - A survey , 2012, Comput. Methods Programs Biomed..

[95]  I. Deary,et al.  Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures , 2005, Journal of anatomy.

[96]  Peter F. Sharp,et al.  Evaluation of a System for Automatic Detection of Diabetic Retinopathy From Color Fundus Photographs in a Large Population of Patients With Diabetes , 2008, Diabetes Care.

[97]  R. Klein,et al.  The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. , 1998, Ophthalmology.

[98]  J M Wardlaw,et al.  Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke , 2010, Neurology.

[99]  Ronald Klein,et al.  The relation of retinal vessel caliber to the incidence and progression of diabetic retinopathy: XIX: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. , 2004, Archives of ophthalmology.

[100]  J. Sepulcre,et al.  RETINAL NERVE FIBER LAYER IS ASSOCIATED WITH BRAIN ATROPHY IN MULTIPLE SCLEROSIS , 2008, Neurology.

[101]  H. Grossniklaus Cerebral white matter lesions, retinopathy, and incident clinical stroke. Wong TY,∗ Klein R, Sharrett AR, Couper DJ, Klein BEK, Liao DP, Hubbard LD, Mosley TH, for the ARIC investigators. JAMA 2002;288:67–74 , 2002 .

[102]  Emanuele Trucco,et al.  Modeling the Tortuosity of Retinal Vessels: Does Caliber Play a Role? , 2010, IEEE Transactions on Biomedical Engineering.

[103]  Mong-Li Lee,et al.  The role of domain knowledge in the detection of retinal hard exudates , 2001, Proceedings of the 2001 IEEE Computer Society Conference on Computer Vision and Pattern Recognition. CVPR 2001.

[104]  J. Wardlaw,et al.  What causes lacunar stroke? , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[105]  T. Wong,et al.  Retinal pathology as biomarker for cognitive impairment and Alzheimer's disease , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[106]  Eduardo Fernández,et al.  Webvision: The Organization of the Retina and Visual System , 1995 .

[107]  I. Deary,et al.  Retinal image analysis: Concepts, applications and potential , 2006, Progress in Retinal and Eye Research.

[108]  R. Klein,et al.  Retinal vessel diameter and cardiovascular mortality: pooled data analysis from two older populations. , 2007, European heart journal.

[109]  Hiroshi Fujita,et al.  Vertical cup-to-disc ratio measurement for diagnosis of glaucoma on fundus images , 2010, Medical Imaging.