Recent Advances in Clinical Applications of Imaging in Retinal Diseases.

Many diseases that cause visual impairment, as well as systemic conditions, manifest in the posterior segment of the eye. With the advent of high-speed, high-resolution, reliable, and noninvasive imaging techniques, ophthalmologists are becoming more dependent on ocular imaging for disease diagnosis, classification, and management in clinical practice. There are rapid advances on the indications of multimodal retinal imaging techniques, including the application of ultra-widefield fundus angiography, fundus autofluorescence, optical coherence tomography, as well as optical coherence tomography angiography. This review summarizes and highlights the clinical applications, latest indications, and interpretations of multimodal imaging in age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic macular edema, central serous chorioretinopathy, diabetic retinopathy, retinal vein occlusion, and uveitis.

Diagnostic assessment of glaucoma and non-glaucomatous optic neuropathies via optical texture analysis of the retinal nerve fibre layer.

The clinical diagnostic evaluation of optic neuropathies relies on the analysis of the thickness of the retinal nerve fibre layer (RNFL) by optical coherence tomography (OCT). However, false positives and false negatives in the detection of RNFL abnormalities are common. Here we show that an algorithm integrating measurements of RNFL thickness and reflectance from standard wide-field OCT scans can be used to uncover the trajectories and optical texture of individual axonal fibre bundles in the retina and to discern distinctive patterns of loss of axonal fibre bundles in glaucoma, compressive optic neuropathy, optic neuritis and non-arteritic anterior ischaemic optic neuropathy. Such optical texture analysis can detect focal RNFL defects in early optic neuropathy, as well as residual axonal fibre bundles in end-stage optic neuropathy that were indiscernible by conventional OCT analysis and by red-free RNFL photography. In a diagnostic-performance study, optical texture analysis of the RNFL outperformed conventional OCT in the detection of glaucoma, as defined by visual-field testing or red-free photography. Our findings show that optical texture analysis of the RNFL for the detection of optic neuropathies is highly sensitive and specific.

Referral for disease-related visual impairment using retinal photograph-based deep learning: a proof-of-concept, model development study.

BACKGROUND: In current approaches to vision screening in the community, a simple and efficient process is needed to identify individuals who should be referred to tertiary eye care centres for vision loss related to eye diseases. The emergence of deep learning technology offers new opportunities to revolutionise this clinical referral pathway. We aimed to assess the performance of a newly developed deep learning algorithm for detection of disease-related visual impairment. METHODS: In this proof-of-concept study, using retinal fundus images from 15 175 eyes with complete data related to best-corrected visual acuity or pinhole visual acuity from the Singapore Epidemiology of Eye Diseases Study, we first developed a single-modality deep learning algorithm based on retinal photographs alone for detection of any disease-related visual impairment (defined as eyes from patients with major eye diseases and best-corrected visual acuity of <20/40), and moderate or worse disease-related visual impairment (eyes with disease and best-corrected visual acuity of <20/60). After development of the algorithm, we tested it internally, using a new set of 3803 eyes from the Singapore Epidemiology of Eye Diseases Study. We then tested it externally using three population-based studies (the Beijing Eye study [6239 eyes], Central India Eye and Medical study [6526 eyes], and Blue Mountains Eye Study [2002 eyes]), and two clinical studies (the Chinese University of Hong Kong's Sight Threatening Diabetic Retinopathy study [971 eyes] and the Outram Polyclinic Study [1225 eyes]). The algorithm's performance in each dataset was assessed on the basis of the area under the receiver operating characteristic curve (AUC). FINDINGS: In the internal test dataset, the AUC for detection of any disease-related visual impairment was 94·2% (95% CI 93·0-95·3; sensitivity 90·7% [87·0-93·6]; specificity 86·8% [85·6-87·9]). The AUC for moderate or worse disease-related visual impairment was 93·9% (95% CI 92·2-95·6; sensitivity 94·6% [89·6-97·6]; specificity 81·3% [80·0-82·5]). Across the five external test datasets (16 993 eyes), the algorithm achieved AUCs ranging between 86·6% (83·4-89·7; sensitivity 87·5% [80·7-92·5]; specificity 70·0% [66·7-73·1]) and 93·6% (92·4-94·8; sensitivity 87·8% [84·1-90·9]; specificity 87·1% [86·2-88·0]) for any disease-related visual impairment, and the AUCs for moderate or worse disease-related visual impairment ranged between 85·9% (81·8-90·1; sensitivity 84·7% [73·0-92·8]; specificity 74·4% [71·4-77·2]) and 93·5% (91·7-95·3; sensitivity 90·3% [84·2-94·6]; specificity 84·2% [83·2-85·1]). INTERPRETATION: This proof-of-concept study shows the potential of a single-modality, function-focused tool in identifying visual impairment related to major eye diseases, providing more timely and pinpointed referral of patients with disease-related visual impairment from the community to tertiary eye hospitals. FUNDING: National Medical Research Council, Singapore.

Screening and identifying hepatobiliary diseases through deep learning using ocular images: a prospective, multicentre study.

BACKGROUND: Ocular changes are traditionally associated with only a few hepatobiliary diseases. These changes are non-specific and have a low detection rate, limiting their potential use as clinically independent diagnostic features. Therefore, we aimed to engineer deep learning models to establish associations between ocular features and major hepatobiliary diseases and to advance automated screening and identification of hepatobiliary diseases from ocular images. METHODS: We did a multicentre, prospective study to develop models using slit-lamp or retinal fundus images from participants in three hepatobiliary departments and two medical examination centres. Included participants were older than 18 years and had complete clinical information; participants diagnosed with acute hepatobiliary diseases were excluded. We trained seven slit-lamp models and seven fundus models (with or without hepatobiliary disease [screening model] or one specific disease type within six categories [identifying model]) using a development dataset, and we tested the models with an external test dataset. Additionally, we did a visual explanation and occlusion test. Model performances were evaluated using the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and F1* score. FINDINGS: Between Dec 16, 2018, and July 31, 2019, we collected data from 1252 participants (from the Department of Hepatobiliary Surgery of the Third Affiliated Hospital of Sun Yat-sen University, the Department of Infectious Diseases of the Affiliated Huadu Hospital of Southern Medical University, and the Nantian Medical Centre of Aikang Health Care [Guangzhou, China]) for the development dataset; between Aug 14, 2019, and Jan 31, 2020, we collected data from 537 participants (from the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-sen University and the Huanshidong Medical Centre of Aikang Health Care [Guangzhou, China]) for the test dataset. The AUROC for screening for hepatobiliary diseases of the slit-lamp model was 0·74 (95% CI 0·71-0·76), whereas that of the fundus model was 0·68 (0·65-0·71). For the identification of hepatobiliary diseases, the AUROCs were 0·93 (0·91-0·94; slit-lamp) and 0·84 (0·81-0·86; fundus) for liver cancer, 0·90 (0·88-0·91; slit-lamp) and 0·83 (0·81-0·86; fundus) for liver cirrhosis, and ranged 0·58-0·69 (0·55-0·71; slit-lamp) and 0·62-0·70 (0·58-0·73; fundus) for other hepatobiliary diseases, including chronic viral hepatitis, non-alcoholic fatty liver disease, cholelithiasis, and hepatic cyst. In addition to the conjunctiva and sclera, our deep learning model revealed that the structures of the iris and fundus also contributed to the classification. INTERPRETATION: Our study established qualitative associations between ocular features and major hepatobiliary diseases, providing a non-invasive, convenient, and complementary method for hepatobiliary disease screening and identification, which could be applied as an opportunistic screening tool. FUNDING: Science and Technology Planning Projects of Guangdong Province; National Key R&D Program of China; Guangzhou Key Laboratory Project; National Natural Science Foundation of China.

Profile of retinal nerve fibre layer symmetry in a multiethnic Asian population: the Singapore Epidemiology of Eye Diseases study.

BACKGROUND: To examine the normative profile and determinants of retinal nerve fibre layer (RNFL) symmetry in a non-glaucoma, multiethnic Asian population. METHODS: Chinese, Malay and Indian adults aged ≥40 years were recruited from the Singapore Epidemiology of Eye Diseases study. Participants underwent standardised systemic and ocular examinations. RNFL thickness was obtained using a spectral-domain optical coherence tomography (Cirrus HD-OCT). RNFL symmetry (in %) was calculated based on Pearson correlation coefficient between the RNFL thickness profiles of the right and left eyes. Multivariable linear regression analysis was used to investigate the associations between ocular and systemic factors with RNFL symmetry. RESULTS: 4211 participants (1227 Chinese, 1245 Malays, 1739 Indians) were included. The mean RNFL symmetry was 86.7%±8.5% in Chinese, 84.7%±10.2% in Malays and 84.0%±10.7% in Indians. The fifth percentile limit of RNFL symmetry was 71.2% in Chinese, 65.0% in Malays and 62.0% in Indians. In multivariable analysis adjusting for age, gender, ethnicity, hypertension, diabetes, hyperlipidaemia, intereye absolute differences in intraocular pressure (IOP), axial length and disc area, Malays (ß=-0.9; p=0.03) and Indians (ß=-1.76; p<0.001) were found to have lower RNFL symmetry compared with Chinese. Older age, greater intereye differences in IOP, axial length and disc area were significantly associated with lower RNFL symmetry (all p≤0.003). CONCLUSIONS: In non-glaucoma individuals, intereye RNFL profile is less symmetric in Malays and Indians than that in Chinese. This also suggests that current commercial optical coherence tomography's deployment of a single, universal RNFL symmetry cut-off for glaucoma detection is flawed, and ethnic-specific cut-off is warranted.

Racial differences and determinants of macular thickness profiles in multiethnic Asian population: the Singapore Epidemiology of Eye Diseases Study.

AIM: To evaluate racial differences, and ocular and systemic determinants of macular thickness (MT), measured by spectral-domain optical coherence tomography (SD-OCT) in a normal multiethnic Asian population. METHOD: MT was measured from a 6×6 mm2 central macular area using the Cirrus high-definition OCT (HD-OCT) (Carl Zeiss Meditec, Dublin, CA). The associations between ocular and systemic factors with MT were evaluated using linear regression analyses with generalised estimating equation models to account for intereye correlation. RESULTS: 7447 healthy eyes (2577 Chinese, 2072 Malays and 2798 Indians) of 4510 subjects were included. Multivariable analysis showed that older age (per decade, ß=-4.39), female gender (ß=-5.74), diabetes (ß=-1.10), chronic kidney disease (CKD) (ß=-3.21), longer axial length (per mm, ß=-2.34), flatter corneal curvature (per mm, ß=-1.79) and presence of cataract (ß=-0.94) were associated with thinner overall average MT (OMT) (all p≤0.026); higher total cholesterol (ß=0.44; p=0.010) was associated with thicker OMT. All these factors were also associated with thinner central subfield MT (CSMT) (all p≤0.001), except for cataract, total cholesterol and CKD. Meanwhile, longer axial length (ß=2.51; p<0.001) was associated with thicker CSMT. OMT (mean±SD) was thickest in Chinese (279.9±12.5 µm), followed by Malays (276.5±13.7 µm) and Indians (272.4±13.1 µm), with p≤0.003 for all interethnic comparisons. Similar trend was observed for CSMT. CONCLUSION: There are interethnic differences in MT profile among Asians, particularly between Chinese and Indians. Ocular and systemic factors affect MT measurements as well. This Asian-specific information may be incorporated into existing clinical interpretation of macular OCT scans to aid in improving the diagnostic and monitoring accuracy of macular diseases among Asians.

Retinal microvasculature changes in amyloid-negative subcortical vascular cognitive impairment compared to amyloid-positive Alzheimer's disease.

BACKGROUND AND PURPOSE: To investigate small vessel abnormalities in patients with cognitive impairment, we compared retinal microvascular alterations between patients with cognitive impairment related to Alzheimer's disease (ADCI) and those with subcortical vascular cognitive impairment (SVCI). METHODS: We prospectively recruited 29 amyloid-positive ADCI patients, 28 amyloid-negative SVCI patients that were confirmed by 11C-PiB-PET scan and 34 individuals with normal cognition (NC). The three groups were compared in terms of retinal vascular variables (retinal fractal dimension, vascular caliber, tortuosity and branching angle) by using a semi-automated, computer-assisted analysis of digital fundus photographs. We also investigated the relationship between retinal variables and white matter hyperintensities (WMH) on MRI. RESULTS: Compared to NC individuals, the SVCI patients had smaller total and arteriolar fractal dimensions, whereas there was no significant difference of fractal dimension between ADCI and NC. Other retinal variables did not differ among the three groups. A significant correlation existed between fractal dimension and WMH volume. CONCLUSIONS: Retinal microvascular alterations, especially retinal fractal dimension, may be useful markers that reflect cerebral microvascular changes in patients with SVCI as opposed to ADCI, who had no definite difference in retinal variables compared to the NC group.

Effects of bariatric surgery on retinal microvascular architecture in obese patients.

STUDY AIM: Retinal microvasculature changes reflect systemic small vessel damage from obesity. The impact of bariatric surgery induced weight loss on the microvasculature is relatively unknown. We hypothesized that weight loss following bariatric surgery would be associated with improved structural changes in the retinal microvasculature, reflecting an overall improvement in microvascular health. METHODS: The study included 22 obese subjects scheduled for bariatric surgery (laparoscopic Roux-en-Y gastric bypass or a sleeve gastrectomy) and 15 lean, age-matched controls. Ophthalmic examination, including fundus photography, was performed at baseline and 6-months. Retinal microvasculature caliber was analysed quantitatively using a semi-automated computer program and summarized as central retinal artery equivalent (CRAE) and venular equivalent (CRVE). RESULTS: Mean weight loss at 6 months was 26.1 kg ± 8 kg in the bariatric surgery group. Retinal artery caliber increased (136.0 ± 1.4 to 141.4 ± 1.4 µm, p = 0.013) and venular caliber decreased (202.9 ± 1.9 to 197.3 ± 1.9 µm, p = 0.046) in the bariatric surgery group by 6 months, with no change in arteriolar (136.6 ± 1.1 to 134.5 ± 1.2, p = 0.222) or venular (195.1 ± 2.1 to 193.3 ± 2.2, p = 0.550) caliber in the control group. The arteriolar to venular ratio increased in the bariatric surgery group, with no change in the control group at 6 months. CONCLUSIONS: The findings suggest obesity-related microvascular changes are reversible after bariatric surgery-induced weight loss. The capacity for the retinal microvasculature to improve following bariatric surgery suggests plasticity of the human microvasculature early in the disease course.

Correlation of Color Fundus Photograph Grading with Risks of Early Age-related Macular Degeneration by using Automated OCT-derived Drusen Measurements.

We evaluated automated OCT-derived drusen volume measures in a population-based study (n = 4,512) aged ≥40 years, and its correlation with conventional color fundus photographs (CFP)-derived early AMD features. Participants had protocol-based assessment to capture medical and ocular history, genotyping for SNPs in CFH, ARMS2, and CETP, CFP-based AMD grading and automated drusen volume based on SD-OCT using built-in software (Cirrus OCT advanced RPE analysis software). Significantly fewer eyes with early AMD features (drusen, hyperpigmentation, soft or reticular drusen) had drusen volume = 0 mm3 (p < 0.001). In eyes with drusen volume > 0 mm3, increasing AMD severity was associated with increase in drusen volume (correlation coefficient 0.17, p < 0.001). However 220 (59.14%) of 372 participants with AMD based on CFP grading had drusen volume = 0 mm3. Factors associated with drusen volume included age (OR 1.42 per 5 years, 95% confidence interval [CI] 2.76, 4.48), systolic blood pressure (OR1.00, 95% CI 1.00, 1.01), ethnic Malay (OR 1.54, 95% CI 1.29, 1.83) and Chinese (OR 1.66, 95% CI 1.37, 2.01) compared to Indian. The ARMS2 rs10490924 T allele was associated with increased drusen volume in subjects with AMD (multivariable adjusted OR1.54, 95% CI 1.08, 2.19). Automated OCT-derived drusen volume is correlated with CFP-based AMD grading in many, but not all subjects. However the agreement is not good. These two modalities provide complementary information and should be incorporated into future studies.

Development and Validation of a Deep Learning System for Diabetic Retinopathy and Related Eye Diseases Using Retinal Images From Multiethnic Populations With Diabetes.

Importance: A deep learning system (DLS) is a machine learning technology with potential for screening diabetic retinopathy and related eye diseases. Objective: To evaluate the performance of a DLS in detecting referable diabetic retinopathy, vision-threatening diabetic retinopathy, possible glaucoma, and age-related macular degeneration (AMD) in community and clinic-based multiethnic populations with diabetes. Design, Setting, and Participants: Diagnostic performance of a DLS for diabetic retinopathy and related eye diseases was evaluated using 494 661 retinal images. A DLS was trained for detecting diabetic retinopathy (using 76 370 images), possible glaucoma (125 189 images), and AMD (72 610 images), and performance of DLS was evaluated for detecting diabetic retinopathy (using 112 648 images), possible glaucoma (71 896 images), and AMD (35 948 images). Training of the DLS was completed in May 2016, and validation of the DLS was completed in May 2017 for detection of referable diabetic retinopathy (moderate nonproliferative diabetic retinopathy or worse) and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse) using a primary validation data set in the Singapore National Diabetic Retinopathy Screening Program and 10 multiethnic cohorts with diabetes. Exposures: Use of a deep learning system. Main Outcomes and Measures: Area under the receiver operating characteristic curve (AUC) and sensitivity and specificity of the DLS with professional graders (retinal specialists, general ophthalmologists, trained graders, or optometrists) as the reference standard. Results: In the primary validation dataset (n = 14 880 patients; 71 896 images; mean [SD] age, 60.2 [2.2] years; 54.6% men), the prevalence of referable diabetic retinopathy was 3.0%; vision-threatening diabetic retinopathy, 0.6%; possible glaucoma, 0.1%; and AMD, 2.5%. The AUC of the DLS for referable diabetic retinopathy was 0.936 (95% CI, 0.925-0.943), sensitivity was 90.5% (95% CI, 87.3%-93.0%), and specificity was 91.6% (95% CI, 91.0%-92.2%). For vision-threatening diabetic retinopathy, AUC was 0.958 (95% CI, 0.956-0.961), sensitivity was 100% (95% CI, 94.1%-100.0%), and specificity was 91.1% (95% CI, 90.7%-91.4%). For possible glaucoma, AUC was 0.942 (95% CI, 0.929-0.954), sensitivity was 96.4% (95% CI, 81.7%-99.9%), and specificity was 87.2% (95% CI, 86.8%-87.5%). For AMD, AUC was 0.931 (95% CI, 0.928-0.935), sensitivity was 93.2% (95% CI, 91.1%-99.8%), and specificity was 88.7% (95% CI, 88.3%-89.0%). For referable diabetic retinopathy in the 10 additional datasets, AUC range was 0.889 to 0.983 (n = 40 752 images). Conclusions and Relevance: In this evaluation of retinal images from multiethnic cohorts of patients with diabetes, the DLS had high sensitivity and specificity for identifying diabetic retinopathy and related eye diseases. Further research is necessary to evaluate the applicability of the DLS in health care settings and the utility of the DLS to improve vision outcomes.

Repeatability and Reproducibility of Retinal Neuronal and Axonal Measures on Spectral-Domain Optical Coherence Tomography in Patients with Cognitive Impairment.

BACKGROUND: With increasing interest in determining if measurement of retinal neuronal structure with spectral-domain optical coherence tomography (SD-OCT) is useful in accessing neurodegenerative process in cognitive decline and development of dementia, it is important to evaluate whether the SD-OCT measurements are repeatable and reproducible in these patients. METHODS: This is a retrospective cohort study. Patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) with no change in global clinical dementia rating (CDR) score at 1-year follow-up were eligible to be included. Ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL) parameters were measured with SD-OCT at baseline, 6-month, and 1-year follow-up visits. At baseline, SD-OCT scans were repeated to access intra-visit repeatability of the SD-OCT measurement. SD-OCT measurement over three visits was used to access inter-visit reproducibility. We calculated intraclass correlation coefficients (ICC) and coefficients of variation (CoVs). RESULTS: We included 32 patients with stable AD and 29 patients with stable MCI in the final analysis. For GC-IPL measures, the average intra-visit ICC was 0.969 (range: 0.948-0.985), and CoV was 1.81% (range: 1.14-2.40); while the average inter-visit ICC was 0.968 (0.941-0.985), and CoV was 1.91% (range: 1.24-2.32). The average ICC and CoV of intra-visit RNFL measured were 0.965 (range: 0.937-0.986) and 2.32% (range: 1.34-2.90%), respectively. The average ICC and CoV of inter-visit RNFL measures were 0.927 (range: 0.845-0.961) and 3.83% (range: 2.71-5.25%), respectively. CONCLUSION: Both GC-IPL and RNFL measurements had good intra-visit repeatability and inter-visit reproducibility over 1 year in elderly patients with no decline in cognitive function, suggesting that SD-OCT is a reliable tool to assess neurodegenerative process over time.

Retinal Vascular Imaging Markers and Incident Chronic Kidney Disease: A Prospective Cohort Study.

Retinal microvascular changes indicating microvascular dysfunction have been shown to be associated with chronic kidney disease (CKD) in cross-sectional studies, but findings were mixed in prospective studies. We aimed to evaluate the relationship between retinal microvascular parameters and incident CKD in an Asian population. We examined 1256 Malay adults aged 40-80 years from the Singapore Malay Eye Study, who attended both the baseline (2004-07) and the follow-up (2011-13) examinations and were free of prevalent CKD. We measured quantitative retinal vascular parameters (arteriolar and venular calibre, tortuosity, fractal dimension and branching angle) using a computer-assisted program (Singapore I Vessel Assessment, SIVA) and retinopathy (qualitative parameter) using the modified Airlie house classification system from baseline retinal photographs. Incident CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 + 25% decrease in eGFR during follow-up. Over a median follow-up period of 6 years, 78 (6.21%) developed CKD (70.5% had diabetes). In multivariable models, smaller retinal arterioles (hazards ratio [95% confidence interval] = 1.34 [1.00-1.78]), larger retinal venules (2.35 [1.12-5.94] and presence of retinopathy (2.54 [1.48-4.36]) were associated with incident CKD. Our findings suggest that retinal microvascular abnormalities may reflect subclinical renal microvascular abnormalities involved in the development of CKD.

Retinal vascular geometry and 6 year incidence and progression of diabetic retinopathy.

AIMS/HYPOTHESIS: We aimed to examine prospectively the association between a range of retinal vascular geometric variables measured from retinal photographs and the 6 year incidence and progression of diabetic retinopathy. METHODS: We conducted a prospective, population-based cohort study of Asian Malay individuals aged 40-80 years at baseline (n = 3280) who returned for a 6 year follow-up. Retinal vascular geometric variables (tortuosity, branching, fractal dimension, calibre) were measured from baseline retinal photographs using a computer-assisted program (Singapore I Vessel Assessment). Diabetic retinopathy was graded from baseline and follow-up photographs using the modified Airlie House classification system. Incidence of diabetic retinopathy was defined as a severity of ≥15 at follow-up among those without diabetic retinopathy at baseline. Incidence of referable diabetic retinopathy was defined as moderate or severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy or diabetic macular oedema at follow-up in participants who had had no or mild non-proliferative diabetic retinopathy at baseline. Progression of diabetic retinopathy was defined as an increase in severity of ≥2 steps at follow-up. Log-binomial models with an expectation-maximisation algorithm were used to estimate RR adjusting for age, sex, diabetes duration, HbA1c level, BP, BMI, estimated GFR and total and HDL-cholesterol at baseline. RESULTS: A total of 427 individuals with diabetes participated in the baseline and 6 year follow-up examinations. Of these, 19.2%, 7.57% and 19.2% developed incidence of diabetic retinopathy, incidence of referable diabetic retinopathy and diabetic retinopathy progression, respectively. After multivariate adjustment, greater arteriolar simple tortuosity (mean RR [95% CI], 1.34 [1.04, 1.74]), larger venular branching angle (RR 1.26 [1.00, 1.59]) and larger venular branching coefficient (RR 1.26 [1.03, 1.56]) were associated with incidence of diabetic retinopathy. Greater arteriolar simple tortuosity (RR 1.82 [1.32, 2.52]), larger venular branching coefficient (RR 1.46 [1.03, 2.07]), higher arteriolar fractal dimension (RR 1.59 [1.08, 2.36]) and larger arteriolar calibre (RR 1.83 [1.15, 2.90]) were associated with incidence of referable diabetic retinopathy. Greater arteriolar simple tortuosity (RR 1.34 [1.12, 1.61]) was associated with diabetic retinopathy progression. Addition of retinal vascular variables improved discrimination (C-statistic 0.796 vs 0.733, p = 0.031) and overall reclassification (net reclassification improvement 18.8%, p = 0.025) of any diabetic retinopathy risk beyond established risk factors. CONCLUSIONS/INTERPRETATION: Retinal vascular geometry measured from fundus photographs predicted the incidence and progression of diabetic retinopathy in adults with diabetes, beyond established risk factors.

Choroidal structures in polypoidal choroidal vasculopathy, neovascular age-related maculopathy, and healthy eyes determined by binarization of swept source optical coherence tomographic images.

PURPOSE: To evaluate quantitatively the choroidal vascularity in polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (AMD) patients compared to healthy controls. METHODS: All eyes underwent swept source optical coherence tomography (OCT), and choroidal images were binarized into blood vessels lumen and stroma. The choroidal vascular index (CVI) was defined as the ratio of luminal area (LA) over total choroidal area of the subfoveal region with a width of 1500 µm. RESULTS: The study included 73 patients with neovascular AMD or PCV with mean ± standard deviation (SD) age of 71.8 ± 9.3 years, which was older than the mean age of 65.1 ± 10.8 years of 72 healthy eyes from control group (p < 0.01). The 44 PCV eyes had significantly higher mean SFCT of 214.23 ± 95.21 µm than neovascular AMD eyes (172.74 ± 96.48 µm, p = 0.03) and greater luminal area (0.23 ± 0.09 mm2 vs. 0.19 ± 0.08 mm2, p = 0.05). After adjusting for age, axial length, and gender in multivariate regression analysis, the SFCT of PCV and neovascular AMD eyes were not significantly different from healthy eyes (195.55 ± 93.11 µm), but the CVI of both PCV (64.94 ± 5.43%, p = 0.01) and neovascular AMD (62.54 ± 5.57%, p = <0.01) were significantly lower than control (68.53 ± 5.91%). CONCLUSION: Despite physiological changes of choroidal vasculature due to aging, the choroidal morphology is different in PCV, neovascular AMD and healthy eyes, which has implication on disease pathogenesis.

Classification of Exudative Age-Related Macular Degeneration With Pachyvessels on En Face Swept-Source Optical Coherence Tomography.

Purpose: The purpose of this study was to classify exudative maculopathy by the presence of pachyvessels on en face swept-source optical coherence tomography (SSOCT). Methods: Consecutive patients with signs of exudative maculopathy underwent SSOCT, fluorescein and indocyanine green angiography (ICGA), ultra-widefield fundus color photography, and autofluorescence examinations. Images were analyzed in a masked fashion by two sets of four examiners in different sessions: (1) the presence of pachyvessels in en face OCT and (2) features of exudative maculopathy in conventional imaging modalities. Quantitative data obtained were subfoveal choroidal thickness (SFCT) and choroidal vascularity index (CVI), which was the ratio of choroidal vessels lumen area to a specified choroidal area from binarized cross-sectional OCT scans. Results: Pachyvessels was observed in 38 (52.1%) of 73 eyes. The pachyvessels group was associated with younger age (69.1 ± 9.4 years, odds ratio [OR] = 0.95, 95% confidence interval [95% CI] = 0.90-0.97, P = 0.04), presence of polypoidal lesions (OR = 3.27, 95% CI = 1.24-8.62, P = 0.01), increased SFCT (OR = 1.08, 95% CI = 1.02-1.14, P < 0.01), and increased CVI (65.4 ± 5.3, OR = 1.12, 95% CI = 1.02-1.23, P = 0.01). In multivariate regression, CVI significantly correlated with pachyvessels (OR = 1.24, 95% CI = 1.03-1.55, P = 0.04). Conclusions: Exudative maculopathy could be classified based on differences in choroidal vasculature morphology. Current results implied that choroidal hemodynamics may be relevant to variable natural history and treatment response in neovascular AMD and polypoidal choroidal vasculopathy.

Imaging retina to study dementia and stroke.

With increase in life expectancy, the number of persons suffering from common age-related brain diseases, including neurodegenerative (e.g., dementia) and cerebrovascular (e.g., stroke) disease is expected to rise substantially. As current neuro-imaging modalities such as magnetic resonance imaging may not be able to detect subtle subclinical changes (resolution <100-500 µm) in dementia and stroke, there is an urgent need for other complementary techniques to probe the pathophysiology of these diseases. The retina - due to its anatomical, embryological and physiological similarities with the brain - offers a unique and accessible "window" to study correlates and consequences of subclinical pathology in the brain. Retinal components such as the microvasculature and retinal ganglion cell axons can now be visualized non-invasively using different retinal imaging techniques e.g., ocular fundus photography and optical coherence tomography. Advances in retinal imaging may provide new and potentially important insights into cerebrovascular neurodegenerative processes in addition to what is currently possible with neuro-imaging. In this review, we present an overview of the current literature on the application of retinal imaging in the study of dementia and stroke. We discuss clinical implications of these studies, novel state-of-the-art retinal imaging techniques and future directions aimed at evaluating whether retinal imaging can be an additional investigation tool in the study of dementia and stroke.

Comparison of Common Retinal Vessel Caliber Measurement Software and a Conversion Algorithm.

PURPOSE: To compare three commonly used retinal vessel caliber measurement software systems, and propose an algorithm for conversion between measurement systems. METHODS: We used 120 retinal photographs to evaluate the agreement between three commonly used software (Retinal Analysis [RA], Integrative Vessel Analysis [IVAN], and Singapore I Vessel Assessment [SIVA]). Bland-Altman plots were used to evaluate agreement of retinal arteriolar (central retinal artery equivalent, CRAE) and venular (central retinal vein equivalent, CRVE) calibers. Pearson's correlation was used to assess the associations between systemic factors and retinal vessel calibers, and Z-test was used to compare the strength of the correlation coefficients across the three software systems. An algorithm was created to convert measurements, with paired t-test performed to evaluate the differences between SIVA-measured retinal calibers and SIVA-approximates converted from RA- and IVAN-measurements using the algorithm. RESULTS: Differences between SIVA- and RA-measured calibers (CRAE: mean difference [MD] = -21.8 µm, 95% limits of agreement [LOA], -47.3 to 3.7 µm; CRVE: MD = -7.7 µm, 95% LOA, -28.0 to 12.6 µm), SIVA- and IVAN-measured calibers (CRAE: MD = -6.7 µm, 95% LOA, -23.8 to 10.4 µm; CRVE: MD = -18.2 µm 95% LOA, -36.7 to 0.4 µm) were large. However, the strength of correlations between systemic factors with SIVA-measured retinal calibers was not significantly different to that measured using RA and IVAN (P ≥ 0.332). SIVA-approximates converted from RA and IVAN measurements using the proposed algorithm was not significantly different from SIVA-measured calibers (P ≥ 0.20). CONCLUSION: Absolute measurements of retinal vessel calibers vary between three common software systems but associations with systemic factors were similar. TRANSLATIONAL RELEVANCE: The proposed algorithm allowed conversions of RA and IVAN measurements to SIVA-approximates. This conversion is important for future data pooling and establishment of normative values for retinal vascular caliber measurements.

Inter-Relationships Between Retinal Vascular Caliber, Retinal Nerve Fiber Layer Thickness, and Glaucoma: A Mediation Analysis Approach.

PURPOSE: The purpose of this study was to explore the interrelationships among retinal vascular caliber, retinal nerve fiber layer (RNFL), and glaucoma; in particular, whether the relationship between narrower retinal vascular caliber and glaucoma is mediated by thinning of RNFL. METHODS: A total of 9407 participants, including 253 glaucoma and 195 primary open-angle glaucoma (POAG) cases from the Singapore Epidemiology of Eye Diseases Study were included in this study. All participants underwent standardized examinations. Glaucoma was defined according to International Society for Geographical and Epidemiologic Ophthalmology criteria. Logistic regression analyses were used to determine the total direct effects of retinal vascular calibers on glaucoma. Regression-based mediation analyses were used to evaluate the indirect effects of retinal vascular caliber on glaucoma through RNFL thinning. RESULTS: After we adjusted for relevant covariates, narrower retinal arteriolar caliber (per standard deviation [SD], 15.1-µm decrease) was associated with glaucoma (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.06-1.38) and POAG (OR, 1.23; 95% CI, 1.06-1.43). Similarly, narrower retinal venular caliber (per SD, 21.6µm decrease) was associated with glaucoma (OR, 1.51; 95% CI, 1.32-1.73) and POAG (OR, 1.64; 95% CI, 1.41-1.91). In addition, there were significant indirect effects of retinal vascular narrowing on glaucoma through thinning of RNFL (all P < 0.001), with mediated proportion of 36.9% and 12.9% in retinal arteriole- and venule-related analysis, respectively. CONCLUSIONS: Mediation analyses indicated that the effect of retinal vascular narrowing on glaucoma was partially the result of thinning of RNFL. These findings provide additional mechanistic insights linking retinal vascular narrowing and glaucoma.

Joint Effect of Early Microvascular Damage in the Eye &Kidney on Risk of Cardiovascular Events.

Microalbuminuria is associated with an increased risk of cardiovascular disease (CVD), but not all individuals require treatment. Retinal microvascular abnormalities and microalbuminuria reflect early systemic microvascular changes. We examined the joint effect of retinal abnormalities and microalbuminuria on CVD risk in an Asian cohort. We conducted a prospective, population-based study. Retinal abnormalities were defined as presence of retinopathy and/or retinal venular widening. Microalbuminuria was defined as urinary albumin: creatinine ratio between 30-300 mg/g. Incident CVD was defined as newly diagnosed clinical stroke, acute myocardial infarction or CVD death. Cox regression models were performed to determine the associations between retinal abnormalities and microalbuminuria with risk of CVD, while controlling for established risk factors. 3,496 participants (aged ≥ 40) were free of prevalent CVD. During the follow-up (5.8 years), 126 (3.60%) participants developed CVD. Persons presenting with both retinal abnormalities and microalbuminuria were 6.71 times (95% CI, 2.68, 16.79) as likely to have incident CVD compared with those without either abnormalities. There was a significant interaction effect between retinal abnormalities and microalbuminuria on incident CVD. Assessment of retinal abnormalities in patients with microalbuminuria may provide additional value in identifying persons at risk of developing CVD.

Assessing the Causality between Blood Pressure and Retinal Vascular Caliber through Mendelian Randomisation.

We aimed to determine the association between blood pressure (BP) and retinal vascular caliber changes that were free from confounders and reverse causation by using Mendelian randomisation. A total of 6528 participants from a multi-ethnic cohort (Chinese, Malays, and Indians) in Singapore were included in this study. Retinal arteriolar and venular caliber was measured by a semi-automated computer program. Genotyping was done using Illumina 610-quad chips. Meta-analysis of association between BP, and retinal arteriolar and venular caliber across three ethnic groups was performed both in conventional linear regression and Mendelian randomisation framework with a genetic risk score of BP as an instrumental variable. In multiple linear regression models, each 10 mm Hg increase in systolic BP, diastolic BP, and mean arterial BP (MAP) was associated with significant decreases in retinal arteriolar caliber of a 1.4, 3.0, and 2.6 µm, and significant decreases in retinal venular caliber of a 0.6, 0.7, and 0.9 µm, respectively. In a Mendelian randomisation model, only associations between DBP and MAP and retinal arteriolar narrowing remained yet its significance was greatly reduced. Our data showed weak evidence of a causal relationship between elevated BP and retinal arteriolar narrowing.