Edmund Arthur

Purpose: To investigate the association between mid-peripheral capillary free zones (CFZs) and retinal structural and functional metrics in diabetics without diabetic retinopathy (DR). Methods: This cross-sectional study included 45 eyes from 28 diabetics without DR and 46 eyes from 31 controls (mean age in both groups, 59 years). Macular optical coherence tomography (OCT) scans were acquired for retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measurements. Thickness measurements were obtained using the Early Treatment of Diabetic Retinopathy Study grid. Retinal mid-peripheral CFZs were computed from OCT angiography images using custom MATLAB software. Retinal function was evaluated as a pilot exploratory objective using full-field flash electroretinography. Correlations between mid-peripheral CFZs and retinal structure and function were assessed using linear mixed-effect models, accounting for the association between eyes, while receiver operating characteristic curves were used to compare the multimodal models. Results: Larger periarteriole CFZs were associated with thinner inner inferior RNFL thickness ( β = −0.48, p = 0.03) in diabetics without DR. Functionally, there was no significant association between the mid-peripheral CFZs and ERG parameters ( p > 0.05) in the no DR group; these findings should be interpreted with caution given the pilot nature of the functional data. The multimodal model of vascular and structural parameters had a modestly improved area under the curve (AUC) and specificity compared to the model of vascular parameters alone (AUC = 0.85 versus 0.83, specificity = 0.65 versus 0.54, respectively). Conclusions: These findings demonstrate that enlarged mid-peripheral periarteriole CFZs are associated with thinner RNFL in diabetics without clinical retinopathy. The multimodal model of vascular and structural metrics showed modestly improved diagnostic ability. This study shows early novel retinal vascular and neural associations in diabetics without clinical retinopathy and demonstrates the potential utility of a multimodal model for discriminating this group from healthy controls.

Background: Perivascular spaces (PVSs) in the brain, when enlarged, serve as indicators of microvascular changes associated with aging and neurodegenerative conditions. Given that the retina shares microvascular similarities with the brain, this study aimed to explore the association between retinal vascular metrics, including mid‐peripheral capillary free zones (CFZs) and MRI‐visible PVS burden. Method: 20 × 20 deg optical coherence tomography angiography images of the central fovea and of paired arterioles, venules, and surrounding capillaries inferior to the fovea of 23 eyes of 14 cognitively unimpaired older adults (mean: 64 years) were acquired. Additionally, a 3T GE PET/MR scanner with a 32‐channel head coil was used to obtain brain images. Retinal metrics, including mid‐peripheral CFZs, vessel diameter, and vessel density, were computed using MATLAB, while the foveal avascular zone (FAZ) was quantified with vendor software lasso tool. An established PVS automatic segmentation algorithm provided whole‐brain PVS characterization, including PVS count, volume, length and width. Correlations were assessed using Pearson correlation and mixed model regression. Result: Although periarteriole CFZ showed a positive trend with PVS width and volume, no significant associations were found. In contrast, perivenule CFZ exhibited a negative trend with median PVS volume and length. Notably, median PVS volume was significantly associated with venule diameter ( r = ‐0.51, p = 0.017), FAZ size ( r = 0.48, p = 0.02), and FAZ effective diameter ( r = 0.44, p = 0.037), while median PVS width was significantly associated with FAZ size ( r = 0.43, p = 0.04). The association between maximum PVS width, minimum PVS length and venule diameter remained significant even after accounting for within‐subject correlation between eyes. Interestingly, age was positively correlated with the total number of perivascular space clusters found in individuals ( r = 0.54, p = 0.008). Conclusion: Our findings suggest that retinal vascular metrics are significantly associated with MRI‐visible PVS burden in cognitively unimpaired older adults, highlighting the potential of using retinal vascular metrics as surrogate markers for brain vascular changes.

Diabetes mellitus (DM) is a debilitating chronic disorder that results in ocular microvascular complications, including diabetic retinopathy (DR) and diabetic macular edema (DME). Early detection and timely intervention for DR and DME are crucial for improving visual outcomes in affected patients. Ophthalmic imaging plays a vital role in the screening, diagnosis, and management of DR and DME. In this review, a comprehensive overview of the imaging modalities frequently utilized in the assessment of DR and DME, encompassing both structural and functional imaging techniques are presented. The key imaging findings that are associated with the various stages of DR and DME are underscored and their diagnostic utility in assessing disease progression and visual function are evaluated. Additionally, we discuss emerging imaging biomarkers that are currently under investigation, which hold significant potential for improving the diagnostic and prognostic capabilities of imaging for DR and DME patients. Finally, the advent of new imaging methods, such as ultrawide-field imaging (UWFI) and deep learning models, which have markedly improved the detection of retinal pathologies are considered.

To compare the width of the mid-peripheral capillary free zones (CFZs; periarteriole and perivenule) between diabetics with no diabetic retinopathy (DR) versus controls. The 20° × 20° optical coherence tomography angiography images of paired arterioles, venules, and their adjacent capillaries within the macular and inferomacular regions of the superficial vascular plexus were obtained from 46 eyes of 28 diabetics with no DR (mean age, 59 years; range, 40-71 years) and 46 eyes of 31 controls (mean age, 59 years; range, 46-78 years). There was no significant difference in age between groups (P = 0.77). The macular and inferomacular images were montaged to generate a wider field of view, followed by the application of a vesselness filter and Otsu thresholding. The mid-peripheral CFZ width was calculated using previously established MATLAB algorithms. Generalized linear mixed models were used to compare the mid-peripheral CFZs between groups, accounting for correlation between eyes. The periarteriole CFZ width was greater in diabetics with no DR (73.3 ± 6.49 µm) compared to controls (67.3 ± 7.08 µm; P < 0.001, Cohen's d = 0.88). Similarly, the perivenule CFZ width was larger in diabetics with no DR (60.8 ± 6.40 µm) compared to controls (54.8 ± 4.58 µm; P < 0.001, Cohens' d = 1.08). Our results demonstrate larger mid-peripheral CFZ width in diabetics with no DR. The mid-peripheral CFZs show promise as a potential novel retinal vascular biomarker for early DR detection. Our study shows the potential clinical utility of the mid-peripheral CFZs for early DR detection.

The potential diagnostic value of plasma amyloidogenic beta residue 42/40 ratio (Aβ42/Aβ40 ratio), neurofilament light (NfL), tau phosphorylated at threonine-181 (p-tau181), and threonine-217 (p-tau217) has been extensively discussed in the literature. We have also previously described the association between retinal biomarkers and preclinical Alzheimer’s disease (AD). The goal of this study was to evaluate the association, and a multimodal model of, retinal and plasma biomarkers for detection of preclinical AD. We included 82 cognitively unimpaired (CU) participants (141 eyes; mean age: 67 years; range: 56–80) from the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS). Blood samples were assessed for concentrations of Aβ42/Aβ40 ratio, NfL, p-tau181, and p-tau217 (ALZpath, Inc.) using Single molecule array (SIMOA) technology. The Spectralis II system (Heidelberg Engineering) was used to acquire macular centered Spectral Domain Optical Coherence Tomography (SD-OCT) images for evaluation of putative retinal gliosis surface area and macular retinal nerve fiber layer (mRNFL) thickness. For all participants, correlations (adjusted for age and correlation between eyes) were assessed between retinal and blood-based biomarkers. A subgroup cohort of 57 eyes from 32 participants with recent Aβ positron emission tomography (PET) results, comprising 18 preclinical patients (Aβ PET + ve, 32 eyes) and 14 controls (Aβ PET -ve, 25 eyes) with a mean age of 69 vs. 66, p = 0.06, was included for the assessment of a multimodal model to distinguish between the two groups. For this subgroup cohort, receiver operating characteristic (ROC) analysis was performed to compare the multimodal model of retinal and plasma biomarkers vs. each biomarker alone to distinguish between the two groups. Significant correlation was found between putative retinal gliosis and p-tau217 in the univariate mixed model (β = 0.48, p = 0.007) but not for the other plasma biomarkers (p > 0.05). This positive correlation was also retained in the multivariate mixed model (β = 0.43, p = 0.022). The multimodal ROC model based on retinal (gliosis area, inner inferior RNFL thickness, inner superior RNFL thickness, and inner nasal RNFL thickness) and plasma biomarkers (p-tau217 and Aβ42/Aβ40 ratio) had an excellent AUC of 0.97 (95% CI = 0.93–1.01; p < 0.001) compared to unimodal models of retinal and plasma biomarkers. Our analyses show the potential of integrating retinal and blood-based biomarkers for improved detection and screening of preclinical AD.

(1) Background: Previously, VESsel GENeration (VESGEN) software was used to map and quantify vascular changes observed on fluorescein angiography (FA) in subjects (n = 15 eyes) with retinal pathology ranging from mild non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR). In the current study, we used VESGEN for the assessment of individuals with early-stage NPDR imaged by FA (Cohort 1) and by optical coherence tomography angiography (OCTA; Cohort 2). (2) Methods: Cohort 1 included type 2 diabetics (T2D), represented 21 eyes (ranging from no DR to moderate DR), and also included nondiabetic controls (NDC; n = 15 eyes). Cohort 2 consisted of 23 eyes from T2D subjects (including no DR subjects and moderate DR subjects) and NDC (n = 18 eyes). (3) Results: In the FA-VESGEN study, total tortuosity (Tv) of microvessels (G ≥ 6) increased in T2D with mild DR compared to the controls. In contrast, the VESGEN analysis of OCTA images showed that vessel length (characterized as density) was lower in T2D subjects before the diagnosis of DR and following the diagnosis of DR when compared to the controls. Additionally, T2D showed a significant decrease in vessel area (density). (4) Conclusions: FA elucidated the vessel morphology of small-generation microvessels to a greater degree than OCTA; however, OCTA identified changes in vessel density better than FA. VESGEN analysis can be used with both standard FA and OCTA to facilitate our understanding of early events in DR, including before the clinical diagnosis of DR.

Purpose: Neuroinflammation plays a significant role in the pathology of Alzheimer's disease (AD). Mouse models of AD and postmortem biopsy of patients with AD reveal retinal glial activation comparable to central nervous system immunoreactivity. We hypothesized that the surface area of putative retinal gliosis observed in vivo using en face optical coherence tomography (OCT) imaging will be larger in patients with preclinical AD versus controls. Methods: The Spectralis II instrument was used to acquire macular centered 20 × 20 and 30 × 25-degrees spectral domain OCT images of 76 participants (132 eyes). A cohort of 22 patients with preclinical AD (40 eyes, mean age = 69 years, range = 60–80 years) and 20 control participants (32 eyes, mean age = 66 years, range = 58–82 years, P = 0.11) were included for the assessment of difference in surface area of putative retinal gliosis and retinal nerve fiber layer (RNFL) thickness. The surface area of putative retinal gliosis and RNFL thickness for the nine sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) map were compared between groups using generalized linear mixed models. Results: The surface area of putative retinal gliosis was significantly greater in the preclinical AD group (0.97 ± 0.55 mm²) compared to controls (0.68 ± 0.40 mm²); F_{(1, 70)} = 4.41, P = 0.039; Cohen's d = 0.61. There was no significant difference between groups for RNFL thickness in the 9 ETDRS sectors, P > 0.05. Conclusions: Our analysis shows greater putative retinal gliosis in preclinical AD compared to controls. This demonstrates putative retinal gliosis as a potential biomarker for AD-related neuroinflammation.

Background: Compared to standard neuro-diagnostic techniques, retinal biomarkers provide a probable low-cost and non-invasive alternative for early Alzheimer’s disease (AD) risk screening. We have previously quantified the periarteriole and perivenule capillary free zones (mid-peripheral CFZs) in cognitively unimpaired (CU) young and older adults as novel metrics of retinal tissue oxygenation. There is a breakdown of the inner retinal blood barrier, pericyte loss, and capillary non-perfusion or dropout in AD leading to potential enlargement of the mid-peripheral CFZs. We hypothesized the mid-peripheral CFZs will be enlarged in CU older adults at high risk for AD compared to low-risk individuals. Methods: 20 × 20° optical coherence tomography angiography images consisting of 512 b-scans, 512 A-scans per b-scan, 12-µm spacing between b-scans, and 5 frames averaged per each b-scan location of the central fovea and of paired major arterioles and venules with their surrounding capillaries inferior to the fovea of 57 eyes of 37 CU low-risk (mean age: 66 years) and 50 eyes of 38 CU high-risk older adults (mean age: 64 years; p = 0.24) were involved in this study. High-risk participants were defined as having at least one APOE e4 allele and a positive first-degree family history of AD while low-risk participants had neither of the two criteria. All participants had Montreal Cognitive Assessment scores ≥ 26. The mid-peripheral CFZs were computed in MATLAB and compared between the two groups. Results: The periarteriole CFZ of the high-risk group (75.8 ± 9.19 µm) was significantly larger than that of the low-risk group (71.3 ± 7.07 µm), p = 0.005, Cohen’s d = 0.55. The perivenule CFZ of the high-risk group (60.4 ± 8.55 µm) was also significantly larger than that of the low-risk group (57.3 ± 6.40 µm), p = 0.034, Cohen’s d = 0.42. There were no significant differences in foveal avascular zone (FAZ) size, FAZ effective diameter, and vessel density between the two groups, all p > 0.05. Conclusions: Our results show larger mid-peripheral CFZs in CU older adults at high risk for AD, with the potential for the periarteriole CFZ to serve as a novel retinal vascular biomarker for early AD risk detection.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non‐invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.