Rigid alignment method for secondary analyses of optical coherence tomography volumes.

Optical coherence tomography (OCT) provides micron level resolution of retinal tissue and is widely used in ophthalmology. Millions of pre-existing OCT images are available from research and clinical databases. Analysis of this data often requires or can benefit significantly from image registration and reduction of speckle noise. One method of reducing noise is to align and average multiple OCT scans together. We propose to use surface feature information and whole volume information to create a novel and simple pipeline that can rigidly align, and average multiple previously acquired 3D OCT volumes from a commercially available OCT device. This pipeline significantly improves both image quality and visualization of clinically relevant image features over single, unaligned volumes from the commercial scanner.

Retinal perfusion is linked to cognition and brain MRI biomarkers in Black Americans.

INTRODUCTION: We investigated whether retinal capillary perfusion is a biomarker of cerebral small vessel disease and impaired cognition among Black Americans, an understudied group at higher risk for dementia. METHODS: We enrolled 96 Black Americans without known cognitive impairment. Four retinal perfusion measures were derived using optical coherence tomography angiography. Neurocognitive assessment and brain magnetic resonance imaging (MRI) were performed. Multiple linear regression analyses were performed. RESULTS: Lower retinal capillary perfusion was correlated with worse Oral Symbol Digit Test (P < = 0.005) and Fluid Cognition Composite scores (P < = 0.02), but not with the Crystallized Cognition Composite score (P > = 0.41). Lower retinal perfusion was also correlated with higher free water and peak width of skeletonized mean diffusivity, and lower fractional anisotropy (all P < 0.05) on MRI (N = 35). DISCUSSION: Lower retinal capillary perfusion is associated with worse information processing, fluid cognition, and MRI biomarkers of cerebral small vessel disease, but is not related to crystallized cognition.

Long-term Follow-up of a Phase 1/2a Clinical Trial of a Stem Cell-Derived Bioengineered Retinal Pigment Epithelium Implant for Geographic Atrophy.

PURPOSE: To report long-term results from a phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in patients with advanced geographic atrophy (GA). DESIGN: A single-arm, open-label phase 1/2a clinical trial approved by the United States Food and Drug Administration. PARTICIPANTS: Patients were 69-85 years of age at the time of enrollment and were legally blind in the treated eye (best-corrected visual acuity [BCVA], ≤ 20/200) as a result of GA involving the fovea. METHODS: The clinical trial enrolled 16 patients, 15 of whom underwent implantation successfully. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion nonimplanted eye served as the control. The primary endpoint was at 1 year; thereafter, patients were followed up at least yearly. MAIN OUTCOME MEASURES: Safety was the primary endpoint of the study. The occurrence and frequency of adverse events (AEs) were determined by scheduled eye examinations, including measurement of BCVA and intraocular pressure and multimodal imaging. Serum antibody titers were collected to monitor systemic humoral immune responses to the implanted cells. RESULTS: At a median follow-up of 3 years, fundus photography revealed no migration of the implant. No unanticipated, severe, implant-related AEs occurred, and the most common anticipated severe AE (severe retinal hemorrhage) was eliminated in the second cohort (9 patients) through improved intraoperative hemostasis. Nonsevere, transient retinal hemorrhages were noted either during or after surgery in all patients as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, results show that implanted eyes were more likely to improve by > 5 letters of BCVA and were less likely to worsen by > 5 letters compared with nonimplanted eyes. CONCLUSIONS: This report details the long-term follow-up of patients with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well tolerated in patients with advanced dry age-related macular degeneration. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinotopic degeneration of the retina and optic tracts in autosomal dominant Alzheimer's disease.

INTRODUCTION: We investigated the correlation between retinal thickness and optic tract integrity in subjects with autosomal dominant Alzheimer's disease (ADAD) causing mutations. METHODS: Retinal thicknesses and diffusion tensor images (DTI) were obtained using optical coherence tomography and magnetic resonance imaging, respectively. The association between retinal thickness and DTI measures was adjusted for age, sex, retinotopy, and correlation between eyes. RESULTS: Optic tract mean diffusivity and axial diffusivity were negatively correlated with retinotopically defined ganglion cell inner plexiform thickness (GCIPL). Fractional anisotropy was negatively correlated with retinotopically defined retinal nerve fiber layer thickness. There was no correlation between outer nuclear layer (ONL) thickness and any DTI measure. DISCUSSION: In ADAD, GCIPL thickness is significantly associated with retinotopic optic tract DTI measures even in minimally symptomatic subjects. Similar associations were not present with ONL thickness or when ignoring retinotopy. We provide in vivo evidence for optic tract changes resulting from ganglion cell pathology in ADAD.

Characterization of spastic paraplegia in a family with a novel PSEN1 mutation.

Spastic paraparesis has been described to occur in 13.7% of PSEN1 mutations and can be the presenting feature in 7.5%. In this paper, we describe a family with a particularly young onset of spastic paraparesis due to a novel mutation in PSEN1 (F388S). Three affected brothers underwent comprehensive imaging protocols, two underwent ophthalmological evaluations and one underwent neuropathological examination after his death at age 29. Age of onset was consistently at age 23 with spastic paraparesis, dysarthria and bradyphrenia. Pseudobulbar affect followed with progressive gait problems leading to loss of ambulation in the late 20s. Cerebrospinal fluid levels of amyloid-ß, tau and phosphorylated tau and florbetaben PET were consistent with Alzheimer's disease. Flortaucipir PET showed an uptake pattern atypical for Alzheimer's disease, with disproportionate signal in posterior brain areas. Diffusion tensor imaging showed decreased mean diffusivity in widespread areas of white matter but particularly in areas underlying the peri-Rolandic cortex and in the corticospinal tracts. These changes were more severe than those found in carriers of another PSEN1 mutation, which can cause spastic paraparesis at a later age (A431E), which were in turn more severe than among persons carrying autosomal dominant Alzheimer's disease mutations not causing spastic paraparesis. Neuropathological examination confirmed the presence of cotton wool plaques previously described in association with spastic parapresis and pallor and microgliosis in the corticospinal tract with severe amyloid-ß pathology in motor cortex but without unequivocal disproportionate neuronal loss or tau pathology. In vitro modelling of the effects of the mutation demonstrated increased production of longer length amyloid-ß peptides relative to shorter that predicted the young age of onset. In this paper, we provide imaging and neuropathological characterization of an extreme form of spastic paraparesis occurring in association with autosomal dominant Alzheimer's disease, demonstrating robust diffusion and pathological abnormalities in white matter. That the amyloid-ß profiles produced predicted the young age of onset suggests an amyloid-driven aetiology though the link between this and the white matter pathology remains undefined.

Variability of Vascular Reactivity in the Retina and Choriocapillaris to Oxygen and Carbon Dioxide Using Optical Coherence Tomography Angiography.

Purpose: To investigate the regional and layer-specific vascular reactivity of the healthy human retina and choriocapillaris to changes in systemic carbon dioxide or oxygen. Methods: High-resolution 3 × 3-mm2 optical coherence tomography angiography (OCTA) images were acquired from the central macula, temporal macula, and peripapillary retina while participants were exposed to three gas breathing conditions-room air, 5%CO2, and 100% O2. OCTA from all three regions were extracted and the apparent skeletonized vessel density (VSD) was assessed. The mean flow deficit sizes (MFDSs) of the choriocapillaris were also assessed. Repeated-measures analysis of variance was used to compare the ratio of intrasubject VSD change induced by the gas conditions from baseline in the superficial retinal layer (SRL) and deep retinal layer (DRL) for each retinal region independently, as well as the MFDS of the choriocapillaris. We also compared the vessel reactivity between the retinal capillaries and the choriocapillaris. Results: The cumulative intrasubject response to the gas conditions differed significantly among regions of the SRL (F(2, 7) = 28.22, P < 0.001), with the temporal macula showing the largest response (15%) compared to the macula (8%) and radial peripapillary capillaries (7%). A similar trend was found in the DRL. The choriocapillaris reactivity was similar between the macula (5.8%) and temporal macula (5.6%). There was also a significant heterogeneity in the layer-specific gas responses, with the DRL showing the largest response (28.2%) and the choriocapillaris showing the smallest response (2.8%). Conclusions: Capillary reactivity to changes in inhaled O2 and CO2 is spatially heterogeneous across the retina but not choriocapillaris.

Ocular and systemic determinants of perifoveal and macular vessel parameters in healthy African Americans.

PURPOSE: To determine the relationship of various systemic and ocular characteristics with perifoveal and macular vessel density in healthy African American eyes. DESIGN: A population-based cross-sectional study of prospectively recruited African Americans ≥40 years of age. Participants underwent 3×3 mm and 6×6 mm macula scans using spectral-domain optical coherence tomography angiography (OCTA), clinical examinations and clinical questionnaires. Participants with glaucoma, severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy and macular oedema were excluded. Custom MATLAB based software quantified vessel area density (VAD) and vessel skeleton density (VSD) in the superficial retinal layer of the macula. Multivariable regression analysis, controlling for inter-eye correlation, was performed to determine systemic and ocular determinants of macular vessel metrics using stepwise selection. Candidate variables included: age, gender, body mass index, history of smoking, history of diabetes, diabetes duration, history of stroke or brain haemorrhage, systolic blood pressure, diastolic blood pressure (DBP), pulse pressure, mean arterial pressure, central subfield thickness (CSFT), visual field mean deviation, intraocular pressure, axial length (AL), mean ocular perfusion pressure and signal strength (SS). RESULTS: A total of 2221 OCTA imaged eyes from 1472 participants were included in this study. Reduced perifoveal and macular VAD and VSD were independently associated with longer AL, reduced SS, reduced CSFT and older age. Male gender and lower DBP were also associated with reduced perifoveal and macular VSD. CONCLUSIONS: When interpreting OCTA images in a clinical setting, it is important to consider the effects ocular and systemic characteristics may have on the macular microcirculation.

Stem cell-derived retinal pigment epithelium transplantation in age-related macular degeneration: recent advances and challenges.

PURPOSE OF REVIEW: Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss in the world with more than 80% of the prevalence accounted for by the nonneovascular (NNAMD) or 'dry' form of the disease. NNAMD does not have any definitive treatment once vision loss has ensued and presents a major unmet medical need. This review will highlight stem cell-based therapies that are a promising form of treatment for advanced NNAMD. RECENT FINDINGS: In the past decade, clinical trials utilizing both induced pluripotent stem cell-derived RPE and human embryonic stem cell-derived RPE have been aggressively pursued as potential treatments of RPE loss and prevention of overlying neurosensory atrophy. While promising preliminary results demonstrating safety and potential efficacy have been published, new challenges have also been identified. These include selecting the most appropriate cell-based therapy, identifying and managing potential immune response as well as characterizing anatomic and functional efficacy. In this review, we will discuss some of these challenges in light of the available data from several early phase clinical trials and discuss the strategies that are being considered to further advance the field. SUMMARY: Cell-based therapies demonstrate promising potential to treat advanced stages of NNAMD. Several early phase clinical trials using both induced pluripotent stem cells (iPSC) and human embryonic stem cell derived (hESC) have demonstrated safety and preliminary signs of efficacy and highlighted remaining challenges which appear surmountable. These challenges include development of selection criteria for use of cell suspensions versus RPE sheets, especially in light of immunological properties of RPE that are intrinsic to the status of RPE differentiation in each of these cell formulations.

OCTA Derived Vessel Skeleton Density Versus Flux and Their Associations With Systemic Determinants of Health.

Purpose: To examine the associations of optical coherence tomography angiography (OCTA)-derived retinal capillary flux with systemic determinants of health. Methods: This is a cross-sectional study of subjects recruited from the African American Eye Disease Study. A commercially available swept-source (SS)-OCTA device was used to image the central 3 × 3 mm macular region. Retinal capillary perfusion was assessed using vessel skeleton density (VSD) and flux. Flux approximates the number of red blood cells moving through vessel segments and is a novel metric, whereas VSD is a previously validated measure commonly used to quantify capillary density. The associations of OCTA derived measures with systemic determinants of health were evaluated using multivariate generalized linear mixed-effects models. Results: A total of 154 eyes from 83 participants were enrolled. Mean VSD and flux were 0.148 ± 0.009 and 0.156 ± 0.016, respectively. In a model containing age, systolic blood pressure, diabetes status, hematocrit, and presence of retinopathy as covariates, there was a negative correlation between VSD and age (P < 0.001) and retinopathy (P = 0.02), but not with hematocrit (P = 0.85) or other factors. There was a positive correlation between flux and hematocrit (P = 0.02), as well as a negative correlation for flux with age (P < 0.001), systolic blood pressure (P = 0.04), and diabetes status (P = 0.02). A 1% decrease in hematocrit was associated with the same magnitude change in flux as ∼1.24 years of aging. Signal strength was associated with flux (P < 0.001), but not VSD (P = 0.51). Conclusions: SS-OCTA derived flux provides additional information about retinal perfusion distinct from that obtained with skeleton density-based measures. Flux is appropriate for detecting subclinical changes in perfusion in the absence of clinical retinopathy.

Survival of an HLA-mismatched, bioengineered RPE implant in dry age-related macular degeneration.

Cell-based therapies face challenges, including poor cell survival, immune rejection, and integration into pathologic tissue. We conducted an open-label phase 1/2a clinical trial to assess the safety and preliminary efficacy of a subretinal implant consisting of a polarized monolayer of allogeneic human embryonic stem cell-derived retinal pigmented epithelium (RPE) cells in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration. Postmortem histology from one subject with very advanced disease shows the presence of donor RPE cells 2 years after implantation by immunoreactivity for RPE65 and donor-specific human leukocyte antigen (HLA) class I molecules. Markers of RPE cell polarity and phagocytosis suggest donor RPE function. Further histologic examination demonstrated CD34+ structures beneath the implant and CD4+, CD68+, and FoxP3+ cells in the tissue. Despite significant donor-host HLA mismatch, no clinical signs of retinitis, vitreitis, vasculitis, choroiditis, or serologic immune response were detected in the deceased subject or any other subject in the study. Subretinally implanted, HLA-mismatched donor RPE cells survive, express functional markers, and do not elicit clinically detectable intraocular inflammation or serologic immune responses even without long-term immunosuppression.

Recommendations for OCT Angiography Reporting in Retinal Vascular Disease: A Delphi Approach by International Experts.

PURPOSE: To develop a consensus nomenclature for reporting OCT angiography (OCTA) findings in retinal vascular disease (e.g., diabetic retinopathy, retinal vein occlusion) by international experts. DESIGN: Delphi-based survey. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Twenty-five retinal vascular disease and OCTA imaging experts. METHODS, INTERVENTION, OR TESTING: A Delphi method of consensus development was used, comprising 2 rounds of online questionnaires, followed by a face-to-face meeting conducted virtually. Twenty-five experts in retinal vascular disease and retinal OCTA imaging were selected to constitute the OCTA Nomenclature in Delphi Study Group for retinal vascular disease. The 4 main areas of consensus were: definition of the parameters of "wide-field (WF)" OCTA, measurement of decreased vascular flow on conventional and WF-OCTA, nomenclature of OCTA findings, and OCTA in retinal vascular disease management and staging. The study end point was defined by the degree of consensus for each question: "strong consensus" was defined as ≥85% agreement, "consensus" as 80% to 84%, and "near consensus" as 70% to 79%. MAIN OUTCOME MEASURES: Consensus and near consensus on OCTA nomenclature in retinal vascular disease. RESULTS: A consensus was reached that a meaningful change in percentage of flow on WF-OCTA imaging should be an increase or decrease ≥30% of the absolute imaged area of flow signal and that a "large area" of WF-OCTA reduced flow signal should also be defined as ≥30% of the absolute imaged area. The presence of new vessels and intraretinal microvascular abnormalities, the foveal avascular zone parameters, the presence and amount of "no-flow areas," and the assessment of vessel density in various retinal layers should be added for the staging and classification of diabetic retinopathy. Decreased flow ≥30% of the absolute imaged area should define an ischemic central retinal vein occlusion. Several other items did not meet consensus requirements or were rejected in the final discussion round. CONCLUSIONS: This study provides international consensus recommendations for reporting OCTA findings in retinal vascular disease, which may help to improve the interpretability and description in clinic and clinical trials. Further validation in these settings is warranted and ongoing. Efforts are continuing to address unresolved questions.

Capillary density and caliber as assessed by optical coherence tomography angiography may be significant predictors of diabetic retinopathy severity.

PURPOSE: To validate retinal capillary density and caliber associations with diabetic retinopathy (DR) severity in different clinical settings. METHODS: This cross-sectional study assessed retinal capillary density and caliber in the superficial retinal layer of 3-mm OCTA scans centered on the fovea. Images were collected from non-diabetic controls and subjects with mild or referable DR (defined DR worse than mild DR) between February 2016 and December 2019 at secondary and tertiary eye care centers. Vessel Skeleton Density (VSD), a measure of capillary density, and Vessel Diameter Index (VDI), a measure of vascular caliber, were calculated from these images. Discriminatory performance of VSD and VDI was evaluated using multivariable logistic regression models predicting DR severity with adjustments for sex, hypertension, and hyperlipidemia. Area under the curve (AUC) was estimated. Model performance was evaluated in two different cohorts. RESULTS: This study included 594 eyes from 385 subjects. Cohort 1 was a training cohort of 509 eyes including 159 control, 155 mild non-proliferative DR (NPDR) and 195 referable DR eyes. Cohort 2 was a validation cohort consisting of 85 eyes including 16 mild NPDR and 69 referable DR eyes. In Cohort 1, addition of VSD and VDI to a model using only demographic data significantly improved the model's AUC for discrimination of eyes with any DR severity from controls (0.91 [95% CI, 0.88-0.93] versus 0.80 [95% CI, 0.76-0.83], p < 0.001) and eyes with referable DR from mild NPDR (0.90 [95% CI, 0.86-0.93] versus 0.69 [95% CI, 0.64-0.75], p < 0.001). The transportability of this regression model was excellent when implemented in Cohort 2 for the referable DR versus mild NPDR comparison. The odds ratio of having any DR compared to control subjects, and referable DR compared to mild DR decreased by 15% (95% CI: 12-18%), and 13% (95% CI: 10-15%), respectively, for every 0.001 unit increase in VSD after adjusting for comorbidities. CONCLUSION: OCTA-derived capillary density has real world clinical value for rapidly assessing DR severity.

Alterations in Retinal Vascular and Oxygen Metrics in Treated and Untreated Proliferative Diabetic Retinopathy: A Case Report.

Proliferative diabetic retinopathy (PDR) is a vision-threatening complication of diabetes. Panretinal photocoagulation (PRP) and anti-vascular endothelial growth factor (anti-VEGF) are approved treatment modalities aimed at regressing neovascularization. Data are lacking about abnormalities in retinal vascular and oxygen metrics before and after combination treatments. A 32-year-old Caucasian male diagnosed with PDR in the right eye was treated by a combination of PRP and multiple anti-VEGF treatments over a 12-month period. The subject underwent optical coherence tomography (OCT) angiography, Doppler OCT, and retinal oximetry before treatment and at 12 months, which was 6 months following the last treatment. Measurements of vascular metrics (vessel density [VD] and mean arterial and venous diameters [DA, DV]) and oxygen metrics (total retinal blood flow [TRBF], inner retinal oxygen delivery [DO2], metabolism [MO2], and extraction fraction [OEF]) were obtained. Both before and after treatments, VD, TRBF, MO2, and DO2 were below the normal lower confidence limits. Additionally, DV and OEF were decreased after treatments. Alterations in retinal vascular and oxygen metrics were reported for the first time in untreated and treated PDR. Future studies are warranted to evaluate the clinical value of these metrics in PDR.

One-Year Follow-Up in a Phase 1/2a Clinical Trial of an Allogeneic RPE Cell Bioengineered Implant for Advanced Dry Age-Related Macular Degeneration.

Purpose: To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD). Methods: The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results. Results: The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant). Conclusions: Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD. Translational Relevance: This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.

Optical Coherence Tomography Angiography-Derived Flux As a Measure of Physiological Changes in Retinal Capillary Blood Flow.

Purpose: To compare optical coherence tomography angiography (OCTA)-derived flux with conventional OCTA measures of retinal vascular density in assessment of physiological changes in retinal blood flow. Methods: Healthy subjects were recruited, and 3 × 3-mm2 fovea-centered scans were acquired using commercially available swept-source OCTA (SS-OCTA) while participants were breathing room air, 100% O2, or 5% CO2. Retinal perfusion was quantified using vessel area density (VAD) and vessel skeleton density (VSD), as well as novel measures of retinal perfusion, vessel area flux (VAF) and vessel skeleton flux (VSF). Flux is proportional to the number of red blood cells moving through a vessel segment per unit time. The percentage change in each measure was compared between the O2 and CO2 gas conditions for images of all vessels (arterioles, venules, and capillaries) and capillary-only images. Statistical significance was determined using paired t-tests and a linear mixed-effects model. Results: Eighty-four OCTA scans from 29 subjects were included (age, 45.9 ± 19.5 years; 14 male, 48.3%). In capillary-only images, the change under the CO2 condition was 168% greater in VAF than in VAD (P = 0.002) and 124% greater in VSF than in VSD (P = 0.004). Similarly, under the O2 condition, the change was 94% greater in VAF than in VAD (P = 0.004) and 57% greater in VSF than in VSD (P = 0.01). Flux measures showed significantly greater change in capillary-only images compared with all-vessels images. Conclusions: OCTA-derived flux measures quantify physiological changes in retinal blood flow at the capillary level with a greater effect size than conventional vessel density measures. Translational Relevance: OCTA-derived flux is a useful measure of subclinical changes in retinal capillary perfusion.

Retinal imaging demonstrates reduced capillary density in clinically unimpaired APOE ε4 gene carriers.

INTRODUCTION: Apolipoprotein E (APOE) ε4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test APOE ε4 effects on human central nervous system capillaries. METHODS: We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations. RESULTS: Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal APOE ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature. DISCUSSION: These results suggest that APOE ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.

Abnormal retinal capillary blood flow in autosomal dominant Alzheimer's disease.

INTRODUCTION: This study characterizes retinal capillary blood flow in subjects with autosomal dominant Alzheimer's disease (ADAD)-causing mutations. METHODS: Carriers of PSEN1 or APP mutations were prospectively recruited and split into early-stage (ES) and late-stage (LS) groups. Controls were normal subjects and non-carriers from the at-risk group. Capillary blood flow was quantified using an optical coherence tomography angiography-based measure of erythrocyte flux through capillary segments. Statistical analyses were adjusted for correlation between two eyes of the same subject. RESULTS: ES carriers had significantly greater capillary blood flow than controls and LS carriers. ES and LS carriers had significantly greater capillary blood flow heterogeneity than controls. There was no difference between capillary blood flow of LS carriers and controls. DISCUSSION: ES ADAD carriers demonstrate increased retinal capillary blood flow and flow heterogeneity compared to controls. These findings support the hypothesis that increased perfusion is a pathophysiologic feature of presymptomatic stages of ADAD.