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To investigate baseline mesopic microperimetry (MP) and spectral domain optical coherence tomography (OCT) in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study.Natural history study METHODS: Setting: 16 clinical sites in Europe and North AmericaStudy Population: Participants with Usher syndrome type 2 (USH2) (N = 80) or autosomal recessive nonsyndromic RP (ARRP) (N = 47) associated with biallelic disease-causing sequence variants in USH2AObservation Procedures: General linear models were used to assess characteristics including disease duration, MP mean sensitivity and OCT intact ellipsoid zone (EZ) area. The associations between mean sensitivity and EZ area with other measures, including best corrected visual acuity (BCVA) and central subfield thickness (CST) within the central 1 mm, were assessed using Spearman correlation coefficients.Mean sensitivity on MP; EZ area and CST on OCT.All participants (N = 127) had OCT, while MP was obtained at selected sites (N = 93). Participants with Usher syndrome type 2 (USH2, N = 80) and nonsyndromic autosomal recessive Retinitis Pigmentosa (ARRP, N = 47) had the following similar measurements: EZ area (median (interquartile range [IQR]): 1.4 (0.4, 3.1) mmLonger disease duration correlated with more severe retinal structure and function abnormalities, and there were associations between MP and OCT metrics. Monitoring changes in retinal structure-function relationships during disease progression will provide important insights into disease mechanism in USH2A-related retinal degeneration.

BACKGROUND AND OBJECTIVE: To explore the association between best-corrected visual acuity (BCVA) improvement and changes in microperimetry (MP) and color vision in patients with nonexudative age-related macular degeneration following administration of two 1.0-mg intravitreal doses of risuteganib. PATIENTS AND METHODS: In a phase 2a, prospective, double-masked, sham-controlled study, eyes with nonexudative age-related macular degeneration and Early Treatment Diabetic Retinopathy Study BCVA between 20/40 and 20/200 were randomized to intravitreal risuteganib (1.0 mg) or sham injection. The risuteganib group received a second 1.0-mg dose, and patients in the sham group crossed over to receive 1.0 mg of risuteganib at week 16. Exploratory endpoints included changes in color vision and mesopic MP. RESULTS: Thirty-nine patients (risuteganib, n = 25; sham, n = 14) completed the study. There was a significant ( P < .05) correlation between BCVA and the total error score (TES) for both Lanthony and Hue Style. Confusion index was close to the criterion for significance ( P = .056) in the risuteganib group. All color vision metrics demonstrated a trend toward improvement in risuteganib responders (BCVA letter gain ≥8 letters) and no change in the nonresponders, with significant differences seen in confusion index between the risuteganib and control group ( P = .0493) and between responders and nonresponders ( P = .0478). MP showed that risuteganib responders improved in mean sensitivity and change in number of loci ≤11 dB and ≤0 dB, whereas nonresponders worsened. CONCLUSION: All color vision and MP parameters tested trended toward improvement in risuteganib-treated patients and risuteganib responders. Statistically significant improvement was evident in two metrics: confusion index (in risuteganib-treated patients and responders) and number of loci with decreased sensitivity (in responders). A significant correlation between BCVA and both TES Lanthony and TES Hue Style in risuteganib patients provides concurrent evidence of objective and subjective improvement of retinal function. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:430–438.]

PURPOSE: To assess baseline differences and longitudinal rate of change in retinal and choroidal imaging parameters between APOE ε4 carriers and non-carriers with normal cognition. DESIGN: Prospective study. SUBJECTS: 413 eyes of 218 individuals with normal cognition aged ≥55 years with known APOE status (98 ε4 carriers, 120 non-carriers). Exclusion criteria included diabetes mellitus, uncontrolled hypertension, glaucoma, and vitreoretinal or neurodegenerative disease. METHODS: Optical coherence tomography (OCT) and OCT angiography (OCTA) was performed at baseline and at 2 years [Zeiss Cirrus HD-OCT 5000 with AngioPlex (Zeiss Meditec, Dublin, CA)]. Groups were compared using sex- and age-adjusted generalized estimating equations. MAIN OUTCOME MEASURES: OCT: retinal nerve fiber layer thickness, macular ganglion cell-inner plexiform layer thickness, central subfield thickness (CST), choroidal vascularity index. OCTA: foveal avascular zone area, perfusion density (PD), vessel density, peripapillary capillary perfusion density and capillary flux index (CFI). Rate of change per year was calculated. RESULTS: At baseline, ε4 carriers had lower CST (p=0.018), PD in the 6mm Early Treatment Diabetic Retinopathy Study (ETDRS) circle (p=0.049), and temporal CFI (p=0.047). Seventy-one ε4 carriers and 78 non-carriers returned at 2 years; at follow-up, the 6mm ETDRS circle (p=0.05) and outer ring (p=0.049) showed lower PD in ε4 carriers, with no differences in rates of change between groups (all p>0.05). CONCLUSIONS: There was exploratory evidence of differences in CST, PD, and peripapillary CFI between APOE ε4 carriers and non-carriers, both with normal cognition. Larger and longer-term studies may further elucidate the potential value of these findings.

A common clinical phenotype of several neurodegenerative and systemic disorders including Alzheimer’s disease and atherosclerosis is the abnormal accumulation of extracellular material, which interferes with routine cellular functions. Similarly, patients with age-related macular degeneration (AMD), the leading cause of vision loss among the aged population, present with extracellular lipid- and protein-filled basal deposits in the back of the eye. While the exact mechanism of growth and formation of these deposits is poorly understood, much has been learned from investigating their composition, providing critical insights into AMD pathogenesis, prevention, and therapeutics. We identified human osteopontin (OPN), a phosphoprotein expressed in a variety of tissues in the body, as a newly discovered component of basal deposits in AMD patients, with a distinctive punctate staining pattern. OPN expression within these lesions, which are associated with AMD disease progression, were found to co-localize with abnormal calcium deposition. Additionally, OPN puncta colocalized with an AMD risk-associated complement pathway protein, but not with apolipoprotein E or vitronectin, two other well-established basal deposit components. Mechanistically, we found that retinal pigment epithelial cells, cells vulnerable in AMD, will secrete OPN into the extracellular space, under oxidative stress conditions, supporting OPN biosynthesis locally within the outer retina. Finally, we report that OPN levels in plasma of aged (non-AMD) human donors were significantly higher than levels in young (non-AMD) donors, but were not significantly different from donors with the different clinical subtypes of AMD. Collectively, our study defines the expression pattern of OPN in the posterior pole as a function of disease, and its local expression as a potential histopathologic biomarker of AMD.

The purpose of the review was to identify structural, functional, blood-based, and other types of biomarkers for early, intermediate, and late nonexudative stages of age-related macular degeneration (AMD) and summarize the relevant data for proof-of-concept clinical trials. AMD is a leading cause of blindness in the aging population, yet no treatments exist for its most common nonexudative form. There are limited data on the diagnosis and progression of nonexudative AMD compared to neovascular AMD. Our objective was to provide a comprehensive, systematic review of recently published biomarkers (molecular, structural, and functional) for early AMD, intermediate AMD, and geographic atrophy and to evaluate the relevance of these biomarkers for use in future clinical trials. A literature search of PubMed, ScienceDirect, EMBASE, and Web of Science from January 1, 1996 to November 30, 2020 and a patent search were conducted. Search terms included “early AMD,” “dry AMD,” “intermediate AMD,” “biomarkers for nonexudative AMD,” “fundus autofluorescence patterns,” “color fundus photography,” “dark adaptation,” and “microperimetry.” Articles were assessed for bias and quality with the Mixed-Methods Appraisal Tool. A total of 94 articles were included (61,842 individuals). Spectral-domain optical coherence tomography was superior at highlighting detailed structural changes in earlier stages of AMD. Fundus autofluorescence patterns were found to be most important in estimating progression of geographic atrophy. Delayed rod intercept time on dark adaptation was the most widely recommended surrogate functional endpoint for early AMD, while retinal sensitivity on microperimetry was most relevant for intermediate AMD. Combinational studies accounting for various patient characteristics and machine/deep-learning approaches were best suited for assessing individualized risk of AMD onset and progression. This systematic review supports the use of structural and functional biomarkers in early AMD and intermediate AMD, which are more reproducible and less invasive than the other classes of biomarkers described. The use of deep learning and combinational algorithms will gain increasing importance in future clinical trials of nonexudative AMD.

Age-related macular degeneration (AMD) is a prevalent disease impeding vision. More recently, AMD has also been linked to cognitive impairment, such as deficits in language and memory skills. In order to better understand the extent of AMD-related changes in the whole brain structure and connectivity, we have conducted an MRI diffusion acquisition study on 40 participants (20 diagnosed with AMD and 20 controls). These acquisitions were then performed again in a follow up two years later. We developed novel analysis methods for diffusion based tractography and connectomes to better determine which, if any, brain region connections saw the greatest changes between the AMD and the age-matched control groups. Using voxel-based analysis, we identified atrophy in AMD participants in the cuneate gyrus, which has been associated with vision, and the left superior temporal gyrus, which has been associated with language, while later acquisitions compounded this with a deficiency in the bilateral cingulate gyrus, itself linked to higher cognition and memory. These regional atrophy findings support that people with AMD experience widespread neuronal degradation that is not limited to retinal neurons. Regions that saw drastically lowered fractional anisotropy among AMD vs. control included the visual cortex, such as the bilateral occipital lobe and the frontoparietal cortex. Tensor Network Principal Component Analysis (TN-PCA) isolated lingual and temporal connections as important differentiators of AMD connectomes compared to controls, thus supporting our morphometric and texture findings in regions related to vision, but also connectopathies of language and memory brain regions. Bundle based analyses in baseline data revealed that the lingual gyrus had greater spread of tracts overall in the AMD participants, which may be explained by prior reorganization in this area, demonstrating a connection between retinal health and lingual structure. Moreover, we noted group differences in the interhemispheric temporal connections, and lingual cerebellar connections, supporting extensive downstream effects of vision loss. Our bundle-based analyses expand the toolset available for neuroimaging-based phenotyping, and reveal widespread changes in AMD participants beyond brain regions and tractography networks directly involved in vision processing, including those involved in language and memory.

Purpose To evaluate the mononuclear cells in the subretinal exudate in Coats' disease. Design Retrospective case series. Methods Five enucleated globes and 1 cytology sample from a patient with Coats' disease and 1 case of chronic retinal detachment following repair of an open globe injury were examined immunohistochemically to identify intraretinal and subretinal exudative cells. The 2 biomarkers were RPE65 for retinal pigment epithelium and CD163 for histiocytes, each tagged with different chromogens, yellow for pigment epithelium and purple for CD163-positive (CD163+) monocytes/histiocytes. Expression levels were sought from both biomarkers together and singly. A color shift to red in the cells' chromogenic reaction indicated the simultaneous presence of the 2 biomarkers. Results Most of the mononuclear cells in Coats' disease samples were CD163+ (purple), and a minority were RPE65+ (yellow). An intermediate number of cells were RPE65+/CD163+ (orange-red). The eye with a chronic retinal detachment had an equal distribution of CD163+ and RPE65+/CD163+ cells. Conclusions RPE has several well-delineated phenotypes and functions. In normal visual physiology, the pigment epithelium supports photoreceptors and participates in their renewal by phagocytosis of the tips of the photoreceptors. The expression of CD163, a feature of hematopoietically derived monocytes, together with RPE65 in the retinal pigment epithelium, supports differentiation toward histiocytes. Yellow staining of detached pigment epithelial cells were rare. The presence of histiocytoid pigment epithelium at the Bruch membrane probably also has implications for macular degeneration.

BackgroundThe macular central 1 mm diameter zone is crucial to patients’ visual acuity, but the long-term natural history of central sparing in eyes with geographic atrophy (GA) is unknown.MethodsWe manually segmented GA in 210 eyes with GA involving central 1 mm diameter zone (mean follow-up=3.8 years) in the Age-Related Eye Disease Study. We measured the residual area in central 1 mm diameter zone and calculated central residual effective radius (CRER) as square root of (residual area/π). A linear mixed-effects model was used to model residual size over time. We added a horizontal translation factor to each data set to account for different durations of GA involving the central zone.ResultsThe decline rate of central residual area was associated with baseline residual area (p=0.008), but a transformation from central residual area to CRER eliminated this relationship (p=0.51). After the introduction of horizontal translation factors to each data set, CRER declined linearly over approximately 13 years (r2=0.80). The growth rate of total GA effective radius was 0.14 mm/year (95% CI 0.12 to 0.15), 3.7-fold higher than the decline rate of CRER (0.038 mm/year, 95% CI 0.034 to 0.042). The decline rate of CRER was 53.3% higher in eyes with than without advanced age-related macular degeneration in the fellow eyes at any visit (p=0.007).ConclusionsCRER in eyes with GA declined linearly over approximately 13 years and may serve as an anatomic endpoint in future clinical trials aiming to preserve the central zone.

Age-related macular degeneration (AMD) is a chronic, multifactorial disease and a leading cause of irreversible blindness in the elderly population in the Western Hemisphere. Among the two major subtypes of AMD, the prevalence of the nonneovascular (dry) type is approximately 85-90% and the neovascular (wet) type is 10-15%. Healthy lifestyle and nutritional supplements of anti-oxidative micronutrients have been shown to delay the progression of dry AMD and lower the risk of development of wet AMD, and anti-vascular endothelial growth factor (anti-VEGF) injections have been shown to improve visual acuity for wet AMD patients. However, to date, there is no approved treatment for geographic atrophy (GA), a debilitating late stage of dry AMD. Thus, this represents a large unmet need in this patient population. This review focuses on the current management and treatment of nonneovascular AMD, the drugs and devices that have been under investigation for the treatment of GA, and the latest clinical trial results. A few therapeutic options have shown initial promising clinical trial results, but failed to show efficacy in larger trials, while others are awaiting future clinical trial results and long-term follow-up to evaluate safety and efficacy.

AMD has been linked to memory deficits, with no established neural mechanisms. In order to describe how resting-state, brain network functional connectivity relates to memory and AMD status in older adults without dementia, we collected resting-state brain fMRI and standardized verbal recall tests from 42 older adults with AMD and 41 age-matched controls. We used seed-based whole brain analysis to quantify the strength of functional connectivity between hubs of the default mode network (DMN) and a network of medial temporal regions relevant for memory. Our results indicated neither memory performance nor network connectivity differed by AMD status. However, the AMD participants exhibited stronger relationships than the controls between memory performance and connectivity from the memory network hub (left parahippocampal) to two other regions: the left temporal pole and the right superior/middle frontal gyri. Also, the connectivity between the medial prefrontal cortex and posterior cingulate cortex of DMN correlated more strongly with memory performance in AMD compared to control. We concluded that stronger brain-behavior correlation in AMD may suggest a role for region-specific connectivity in supporting memory in the context of AMD.

Purpose To assess visual function outcomes to 48 weeks in patients with bilateral geographic atrophy (GA) secondary to age-related macular degeneration included in 2 interventional clinical trials: relationship to baseline lesion size, outcomes by baseline lesion characteristic subgroups, and correlation of visual function outcomes with GA area. Design The Chroma and Spectri studies ( ClinicalTrials.gov identifiers, NCT02247479 and NCT02247531 , respectively) were identically designed phase 3, double-masked, multicenter, randomized, sham injection-controlled clinical trials that evaluated intravitreal lampalizumab in GA. Participants Eligible patients were 50 years of age or older with well-demarcated bilateral GA (lesion size, 1–7 disc areas) without evidence of or previous treatment for choroidal neovascularization in either eye and best-corrected visual acuity (BCVA) letter score of 49 letters or more (≥1 GA lesion within 250 μm of foveal center if BCVA ≥79 letters). Methods Patients (pooled n = 1881) were randomized 2:1:2:1 to lampalizumab every 4 weeks, sham every 4 weeks, lampalizumab every 6 weeks, or sham every 6 weeks. Sham arms were pooled for analysis. Main Outcome Measures Functional end points included change in BCVA from baseline to week 48, low-luminance visual acuity, mesopic microperimetry (number of absolute scotomatous points, mean macular sensitivity), binocular and monocular maximum reading speed, and 2 validated patient-reported outcome measures: Functional Reading Independence Index and 25-item National Eye Institute Visual Function Questionnaire. Results Enlargement of GA area, approximately 2 mm2/year on average across all treatment groups in each study, was accompanied by overall deterioration in all functional end points. No statistically significant differences were found between lampalizumab or sham arms for changes from baseline in functional assessment scores. Of visual function tests, only microperimetry outcomes were correlated moderately with GA lesion area when assessed cross-sectionally at baseline and week 48. Conclusions Chroma and Spectri provide a unique data set of functional end points in GA that are relevant for future clinical trials. Patients with bilateral GA experienced a consistent decline in visual function over 48 weeks, but measures of visual function were not correlated strongly with GA lesion area. It is not possible to predict visual function outcomes from GA lesion size.

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe

Purpose To test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor (CNTF), on progression of macular telangiectasia type 2, a neurodegenerative disease with no proven effective therapy. Design Randomized sham-controlled clinical trial. Participants Ninety-nine study eyes of 67 eligible participants were enrolled. Methods Single-masked randomized clinical trial of 24 months’ duration conducted from May 2014 through April 2017 in 11 clinical centers of retinal specialists in the United States and Australia. Participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure. Main Outcome Measures The primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain (SD) OCT images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups. Results Among the 67 participants who were randomized (mean age, 62±8.9 years; 41 women [61%]; 58 white persons [86%]), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 participants (4 eyes) were found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration than the CNTF-treated eyes. The difference in mean area of photoreceptor loss was 0.05±0.03 mm2 (P = 0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r = 0.86; P Conclusions In participants with macular telangiectasia type 2, a surgical implant that released CNTF into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration. Further research is needed to assess longer-term clinical outcomes and safety.

Topic OCT is a noninvasive tool to measure specific retinal layers in the eye. The relationship of retinal spectral-domain (SD) OCT measurements with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) remains unclear. Hence, we conducted a systematic review and meta-analysis to examine the SD OCT measurements in AD and MCI. Clinical Relevance Current methods of diagnosing early AD are expensive and invasive. Retinal measurements of SD OCT, which are noninvasive, technically simple, and inexpensive, are potential biomarkers of AD. Methods We conducted a literature search in PubMed and Excerpta Medica Database to identify studies published before December 31, 2017, that assessed the associations between AD, MCI, and measurements of SD OCT: ganglion cell–inner plexiform layer (GC-IPL), ganglion cell complex (GCC), macular volume, and choroidal thickness, in addition to retinal nerve fiber layer (RNFL) and macular thickness. We used a random-effects model to examine these relationships. We also conducted meta-regression and assessed heterogeneity, publication bias, and study quality. Results We identified 30 eligible studies, involving 1257 AD patients, 305 MCI patients, and 1460 controls, all of which were cross-sectional studies. In terms of the macular structure, AD patients showed significant differences in GC-IPL thickness (standardized mean difference [SMD], –0.46; 95% confidence interval [CI], –0.80 to –0.11; I2 = 71%), GCC thickness (SMD, –0.84; 95% CI, –1.10 to –0.57; I2 = 0%), macular volume (SMD, –0.58; 95% CI, –1.03 to –0.14; I2 = 80%), and macular thickness of all inner and outer sectors (SMD range, –0.52 to –0.74; all P Conclusions Our results confirmed the associations between retinal measurements of SD OCT and AD, highlighting the potential usefulness of SD OCT measurements as biomarkers of AD.

Age-related macular degeneration (AMD) is a chronic, multifactorial disease and a leading cause of irreversible blindness in the elderly population in the Western Hemisphere. Among the two major subtypes of AMD, the prevalence of the nonneovascular (dry) type is approximately 85-90% and the neovascular (wet) type is 10-15%. Healthy lifestyle and nutritional supplements of anti-oxidative micronutrients have been shown to delay the progression of dry AMD and lower the risk of development of wet AMD, and anti-vascular endothelial growth factor (anti-VEGF) injections have been shown to improve visual acuity for wet AMD patients. However, to date, there is no approved treatment for geographic atrophy (GA), a debilitating late stage of dry AMD. Thus, this represents a large unmet need in this patient population. This review focuses on the current management and treatment of nonneovascular AMD, the drugs and devices that have been under investigation for the treatment of GA, and the latest clinical trial results. A few therapeutic options have shown initial promising clinical trial results, but failed to show efficacy in larger trials, while others are awaiting future clinical trial results and long-term follow-up to evaluate safety and efficacy.

PURPOSE To evaluate the effect of select baseline characteristics on geographic atrophy (GA) progression in eyes receiving intravitreal pegcetacoplan or sham. DESIGN Phase 2 multicenter, randomized, single-masked, sham-controlled trial. METHODS Patients with GA received 15 mg pegcetacoplan monthly or every other month (EOM), or sham injection monthly or EOM for 12 months. Primary efficacy endpoint was change in GA lesion size (square root) from baseline. Post hoc analysis evaluated the effects of age; gender; lesion size, focality, and location (extrafoveal vs foveal); pseudodrusen status; best-corrected visual acuity (BCVA); and low-luminance deficit (LLD) on GA progression at Month 12. RESULTS Of 246 randomized patients, 192 with 12-month data were included in this analysis. Overall mean (standard deviation) change in lesion size (mm) was 0.26 (0.17) (P < .01), 0.27 (0.27) (P

Highlights • AMD patients show weaker connection in the splenium and left optic radiation. • Verbal fluency scores correlate with connection in the splenium and left IFOF/ILF. • AMD is linked with weaker correlations of cognition and white matter connection., Age-related macular degeneration (AMD) is a common retina disease associated with cognitive impairment in older adults. The mechanism(s) that account for the link between AMD and cognitive decline remain unclear. Here we aim to shed light on this issue by investigating whether relationships between cognition and white matter in the brain differ by AMD status. In a direct group comparison of brain connectometry maps from diffusion weighted images, AMD patients showed significantly weaker quantitative anisotropy (QA) than healthy controls, predominantly in the splenium and left optic radiation. The QA of these tracts, however, did not correlate with the visual acuity measure, indicating that this group effect is not directly driven by visual loss. The AMD and control groups did not differ significantly in cognitive performance. Across all participants, better cognitive performance (e.g. verbal fluency) is associated with stronger connectivity strength in white matter tracts including the splenium and the left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. However, there were significant interactions between group and cognitive performance (verbal fluency, memory), suggesting that the relation between QA and cognitive performance was weaker in AMD patients than in controls. This may be explained by unmeasured determinants of performance that are more common or impactful in AMD or by a recruitment bias whereby the AMD group had higher cognitive reserve. In general, our findings suggest that neural degeneration in the brain might occur in parallel to AMD in the eyes, although the participants studied here do not (yet) exhibit overt cognitive declines per standard assessments.

Fundus-controlled perimetry (FCP, also called 'microperimetry') allows for spatially-resolved mapping of visual sensitivity and measurement of fixation stability, both in clinical practice as well as research. The accurate spatial characterization of visual function enabled by FCP can provide insightful information about disease severity and progression not reflected by best-corrected visual acuity in a large range of disorders. This is especially important for monitoring of retinal diseases that initially spare the central retina in earlier disease stages. Improved intra- and inter-session retest-variability through fundus-tracking and precise point-wise follow-up examinations even in patients with unstable fixation represent key advantages of these technique. The design of disease-specific test patterns and protocols reduces the burden of extensive and time-consuming FCP testing, permitting a more meaningful and focused application. Recent developments also allow for photoreceptor-specific testing through implementation of dark-adapted chromatic and photopic testing. A detailed understanding of the variety of available devices and test settings is a key prerequisite for the design and optimization of FCP protocols in future natural history studies and clinical trials. Accordingly, this review describes the theoretical and technical background of FCP, its prior application in clinical and research settings, data that qualify the application of FCP as an outcome measure in clinical trials as well as ongoing and future developments.

Purpose To investigate the topographic distribution of geographic atrophy (GA) and to identify an anatomic endpoint that correlates with visual acuity (VA) in eyes with GA. Design Retrospective analysis of a multicenter, prospective, randomized controlled trial. Participants The Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. Methods We manually delineated GA on 1654 fundus photographs of 365 eyes. We measured GA areas in 9 subfields on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r2 between GA area in the central zone and VA was achieved. We estimated the VA decline rate over 8 years using a linear mixed model. Main Outcome Measures Geographic atrophy area in macular subfields and VA. Results The percentage of area affected by GA declined as a function of retinal eccentricity. GA area was higher in the temporal than the nasal region (1.30 ± 1.75 mm2 vs. 1.10 ± 1.62 mm2; P = 0.005) and in the superior than the inferior region (1.26 ± 1.73 mm2 vs. 1.03 ± 1.53 mm2; P Conclusions The prevalence of GA varies significantly across different macular regions. Although total GA area was associated poorly with VA, GA area in the central 1-mm diameter zone was correlated significantly with VA and may serve as a surrogate endpoint in clinical trials.

Background Previous epidemiologic studies have suggested an association between AMD and AD, and several therapeutic agents are being developed based on this principle. However, prior studies have provided conflicting results due in part to their reliance on clinical diagnoses that are not based on gold-standard histopathology. Objective To use histopathologic standards for diagnosis in order to determine the co-prevalence of AD among patients with and without AMD. Methods This is a cross-sectional study of 157 autopsy ocular specimens from patients with and without AMD that were greater than 75 years of age at death. Sarks staging was used to document the severity of AMD, and Braak and Braak staging was used to assess the severity of AD in corresponding brain specimens. The prevalence of AD within different severities of AMD was determined using univariable and multivariable logistic regression. Results 58% of autopsy eyes had AMD. The prevalence of AD was lower in AMD subjects (63%) compared to non-AMD subjects (73%), even when grouped by severity (all p > 0.15). The likelihood of AD was significantly less in AMD subjects, even after adjusting for age and sex in multivariable analysis (OR 0.47, p = 0.049). Conclusion Histopathologic diagnoses fail to support an increase in prevalence of AD among subjects with AMD, even when disease severity is considered.

In macula-wide analyses, spectral-domain (SD) optical coherence tomography (OCT) features including drusen volume, hyperreflective foci, and OCT-reflective drusen substructures independently predict geographic atrophy (GA) onset secondary to age-related macular degeneration (AMD). We sought to identify SD OCT features in the location of new GA before its onset.Retrospective study.Age-Related Eye Disease Study 2 Ancillary SD OCT Study participants.We analyzed longitudinally captured SD OCT images and color photographs from 488 eyes of 488 participants with intermediate AMD at baseline. Sixty-two eyes with sufficient image quality demonstrated new-onset GA on color photographs during study years 2 through 7. The area of new-onset GA and one size-matched control region in the same eye were segmented separately, and corresponding spatial volumes on registered SD OCT images at the GA incident year and at 2, 3, and 4 years previously were defined. Differences in SD OCT features between paired precursor regions were evaluated through matched-pairs analyses.Localized SD OCT features 2 years before GA onset.Compared with paired control regions, GA precursor regions at 2, 3, and 4 years before (n = 54, 33, and 25, respectively) showed greater drusen volume (P = 0.01, P = 0.003, and P = 0.003, respectively). At 2 and 3 years before GA onset, they were associated with the presence of hypertransmission (P0.001 and P = 0.03, respectively), hyperreflective foci (P0.001 and P = 0.045, respectively), OCT-reflective drusen substructures (P = 0.004 and P = 0.03, respectively), and loss or disruption of the photoreceptor zone, ellipsoid zone, and retinal pigment epithelium (RPE, P0.001 and P = 0.005-0.045, respectively). At 4 years before GA onset, precursor regions were associated with photoreceptor zone thinning (P = 0.007) and interdigitation zone loss (P = 0.045).Evolution to GA is heralded by early local photoreceptor changes and drusen accumulation, detectable 4 years before GA onset. These precede other anatomic heralds such as RPE changes and drusen substructure emergence detectable 1 to 2 years before GA. This study thus identified earlier end points for GA as potential therapeutic targets in clinical trials.

To assess visual function outcomes to 48 weeks in patients with bilateral geographic atrophy (GA) secondary to age-related macular degeneration included in 2 interventional clinical trials: relationship to baseline lesion size, outcomes by baseline lesion characteristic subgroups, and correlation of visual function outcomes with GA area.The Chroma and Spectri studies (ClinicalTrials.gov identifiers, NCT02247479 and NCT02247531, respectively) were identically designed phase 3, double-masked, multicenter, randomized, sham injection-controlled clinical trials that evaluated intravitreal lampalizumab in GA.Eligible patients were 50 years of age or older with well-demarcated bilateral GA (lesion size, 1-7 disc areas) without evidence of or previous treatment for choroidal neovascularization in either eye and best-corrected visual acuity (BCVA) letter score of 49 letters or more (≥1 GA lesion within 250 μm of foveal center if BCVA ≥79 letters).Patients (pooled n = 1881) were randomized 2:1:2:1 to lampalizumab every 4 weeks, sham every 4 weeks, lampalizumab every 6 weeks, or sham every 6 weeks. Sham arms were pooled for analysis.Functional end points included change in BCVA from baseline to week 48, low-luminance visual acuity, mesopic microperimetry (number of absolute scotomatous points, mean macular sensitivity), binocular and monocular maximum reading speed, and 2 validated patient-reported outcome measures: Functional Reading Independence Index and 25-item National Eye Institute Visual Function Questionnaire.Enlargement of GA area, approximately 2 mmChroma and Spectri provide a unique data set of functional end points in GA that are relevant for future clinical trials. Patients with bilateral GA experienced a consistent decline in visual function over 48 weeks, but measures of visual function were not correlated strongly with GA lesion area. It is not possible to predict visual function outcomes from GA lesion size.

IntroductionPrevious studies evaluating the association between clinically diagnosed Alzheimer's disease (AD) and age-related macular degeneration (AMD) have generated conflicting results. This study is the first to assess whether AMD prevalence is higher in AD patients than non-AD controls by using histopathology to definitively diagnose AD.MethodsThis was a retrospective case-control study utilizing diagnostic information extracted from autopsy reports of patients age 75 and above, including 115 with a neuropathological diagnosis of AD and 57 age-matched normal controls.ResultsThe rate of AMD was not significantly higher in AD cases (53.0%) than in controls (59.6%) (z = 0.820, p = 0.794). AMD severity as determined by Sarks score was similar between AD patients and controls (χ2 = 2.96, p = 0.706). There was also no significant association between Braak stage of AD severity and AMD (χ2 = 4.55, p = 0.602).DiscussionNo significant effect of AD diagnosis or pathologic severity on AMD comorbidity was found, suggesting that any shared mechanisms between AMD and AD may be nondeterministic.

PURPOSE: To analyze the potential association between aspirin use and progression of age-related macular degeneration (AMD). DESIGN: Two prospective cohort studies within two controlled clinical trials of oral supplementation for age-related eye disease. PARTICIPANTS: Age-Related Eye Disease Study (AREDS) participants, aged 55 to 80 years, and AREDS2 participants, aged 50 to 85 years. METHODS: Propensity scores for aspirin use were calculated for AREDS and AREDS2 participants, separately, by logistic regression. Of the participants without late AMD (geographic atrophy (GA) or neovascular AMD) in either eye at study baseline, aspirin users were matched 1:1 with non-users by propensity score (separately for AREDS and AREDS2). Proportional hazards regression was performed, adjusting for age, on the matched participants to evaluate associations between aspirin propensity score and progression to late AMD (and its subtypes). MAIN OUTCOME MEASURES: Progression to late AMD on color fundus photographs, graded centrally. RESULTS: Of the 3734 eligible AREDS participants, 1049 (28.1%) were taking aspirin and 2685 (71.9%) were not. The equivalent figures in AREDS2 were 1198 (49.9%) and 1205 (50.1%), respectively. Following matching by propensity score, the characteristics of the users and non-users were similar, in both studies. Of the 1950 matched AREDS participants and 1694 matched AREDS2 participants, over median follow-up of 10.1 years (AREDS) and 5.0 years (AREDS2), the numbers who progressed to late AMD, GA, or neovascular AMD were 454 (23.3%), 345 (17.7%), and 278 (14.3%), respectively, in AREDS, and 643 (38.0%), 402 (24.6%), and 341 (20.1%), in AREDS2. The hazard ratios of progression in quintile 5 (highest propensity for aspirin use) versus 1 (reference) were 1.17 (p=0.35), 1.24 (p=0.25), and 0.95 (p=0.81), respectively, in AREDS, and 1.26 (p=0.09), 1.46 (p=0.03), and 1.12 (p=0.58), in AREDS2. No significant association with progression to late AMD was observed for any quintile 2–5, for any of the three outcomes, in either study. CONCLUSIONS: Aspirin use was not significantly associated with progression to late AMD, or its subtypes, in either the AREDS or the AREDS2. Patients with AMD need not avoid aspirin for this reason, when its use is medically indicated.

PURPOSE The objectives of this study were to evaluate 1) the feasibility of performing computerized tests of low luminance visual acuity (LLVA), cone-specific contrast (Cone Contrast Test [CCT]), contrast sensitivity, and microperimetry and 2) the test-retest repeatability of these outcomes in dry age-related macular degeneration (AMD). METHODS This prospective study enrolled 30 subjects at a single site (8 controls, 8 early AMD, and 12 intermediate AMD). Subjects underwent LLVA, contrast sensitivity, CCT, and microperimetry with eye tracking. Low luminance deficit was defined as best-corrected visual acuity minus LLVA in EDTRS letters. Follow-up testing was administered at approximately 1 month. RESULTS There was high test-retest repeatability at one month for all visual function metrics (intraclass correlations >0.7) except log contrast sensitivity (intraclass correlations 0.6). Compared with controls, patients with intermediate AMD showed significant deficits on best-corrected visual acuity, LLVA, low luminance deficit, percent-reduced threshold on microperimetry, and red CCT (P < 0.05), but not on contrast sensitivity, green and blue CCT. CONCLUSION This pilot study supports the feasibility and reliability of using LLVA, microperimetry, and CCT in early dry AMD. Our data suggest these measures can be used as alternative future clinical trial endpoints. A larger, prospective natural history study of alternative visual function measures in dry AMD is warranted.

Author(s): Birch, David G; Cheng, Peiyao; Duncan, Jacque L; Ayala, Allison R; Maguire, Maureen G; Audo, Isabelle; Cheetham, Janet K; Durham, Todd A; Fahim, Abigail T; Ferris, Frederick L; Heon, Elise; Huckfeldt, Rachel M; Iannaccone, Alessandro; Khan, Naheed W; Lad, Eleonora M; Michaelides, Michel; Pennesi, Mark E; Stingl, Katarina; Vincent, Ajoy; Weng, Christina Y; Foundation Fighting Blindness Consortium Investigator Group | Abstract: PurposeThe purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 (USH2A)-related Retinal Degeneration (RUSH2A) multicenter study.MethodsParticipants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, Nn=n47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models.ResultsIn comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P l 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6nµV; P l 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; Pn=n0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23ndB] vs. [-39, -45, -28ndB]; P l 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated (Pn=n0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders (Pn=n0.04) and duration of visual loss (P l 0.001) also were associated with FST white stimulus.ConclusionsUSH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression.Translational relevanceUsing standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations.

Purpose To report the 1-year progression of visual impairment on psychophysical tests of visual function in patients with early and intermediate age-related macular degeneration (AMD). Design Prospective, observational study. Participants Patients with early and intermediate AMD were enrolled from the existing population at the Duke Eye Center, and healthy age-matched control participants were recruited from family members or friends of the AMD patients and from the Duke Optometry and Comprehensive Eye Clinics. Methods Patients and control participants recruited during the baseline study were assessed at both 6 and 12 months after the initial study visit. Measurements of visual function included best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-luminance deficit (LLD), microperimetry percent-reduced threshold (PRT), microperimetry average threshold (AT), and cone contrast tests (CCTs). Main Outcome Measures Changes in BCVA, LLVA, LLD, microperimetry PRT, microperimetry AT, and CCT results from baseline to 6 months and to 12 months were assessed. Results Eighty-five patients completed the 12-month examination (19 control participants, 27 early AMD patients, and 39 intermediate AMD patients). Longitudinal analysis detected significant changes from baseline within each group in microperimetry PRT and AT and in the intermediate AMD group only for BCVA and CCT results (P Conclusions Microperimetry and CCT are able to detect functional changes resulting from progression of dry AMD within a period as short as 12 months. These functional markers may be useful end points in future clinical trials that assess the effect of potential treatments for AMD.

PURPOSE: To test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor (CNTF), on progression of macular telangiectasia type 2, a neurodegenerative disease with no proven effective therapy. DESIGN: Randomized sham-controlled clinical trial. PARTICIPANTS: Ninety-nine study eyes of 67 eligible participants were enrolled. METHODS: Single-masked randomized clinical trial of 24 months’ duration conducted from May 2014 through April 2017 in 11 clinical centers of retinal specialists in the United States and Australia. Participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure. MAIN OUTCOME MEASURES: The primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain (SD) OCT images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups. RESULTS: Among the 67 participants who were randomized (mean age, 62±8.9 years; 41 women [61%]; 58 white persons [86%]), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 participants (4 eyes) were found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration than the CNTF-treated eyes. The difference in mean area of photoreceptor loss was 0.05±0.03 mm(2) (P = 0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r = 0.86; P < 0.0001). The mean retinal sensitivity loss of the sham group was 45% greater than that of the treated group (decrease, 15.81±8.93 dB; P = 0.07). Reading speed deteriorated in the sham group (−13.9 words per minute) with no loss in the treated group (P = 0.02). Serious adverse ocular effects were found in 2 of 51 persons (4%) in the sham group and 2 of 48 persons (4%) in the treated group. CONCLUSIONS: In participants with macular telangiectasia type 2, a surgical implant that released CNTF into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration. Further research is needed to assess longer-term clinical outcomes and safety.

Alzheimer's disease (AD) and age-related macular degeneration (AMD) are important disorders of aging, but significant challenges remain in diagnosis and therapy. Amyloid-beta (Aβ), found in the brain and a defining feature of AD, has also been observed in the retina in both AD and AMD. While current diagnostic modalities for detecting Aβ in the brain are costly or invasive, Aβ in the retina can be noninvasively and conveniently imaged using modern photonic imaging systems such as optical coherence tomography (OCT). Moreover, since many of these retinal changes occur before degenerative changes can be detected in the brain, ocular amyloid biomarkers could be utilized to detect AD as well as AMD in their earliest stages when therapy may be most effective in halting disease progression. Novel technologies to quantify retinal biomarkers have the potential to facilitate early diagnosis and noninvasive monitoring of disease progression with important therapeutic implications.

OCT is a noninvasive tool to measure specific retinal layers in the eye. The relationship of retinal spectral-domain (SD) OCT measurements with Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains unclear. Hence, we conducted a systematic review and meta-analysis to examine the SD OCT measurements in AD and MCI.Current methods of diagnosing early AD are expensive and invasive. Retinal measurements of SD OCT, which are noninvasive, technically simple, and inexpensive, are potential biomarkers of AD.We conducted a literature search in PubMed and Excerpta Medica Database to identify studies published before December 31, 2017, that assessed the associations between AD, MCI, and measurements of SD OCT: ganglion cell-inner plexiform layer (GC-IPL), ganglion cell complex (GCC), macular volume, and choroidal thickness, in addition to retinal nerve fiber layer (RNFL) and macular thickness. We used a random-effects model to examine these relationships. We also conducted meta-regression and assessed heterogeneity, publication bias, and study quality.We identified 30 eligible studies, involving 1257 AD patients, 305 MCI patients, and 1460 controls, all of which were cross-sectional studies. In terms of the macular structure, AD patients showed significant differences in GC-IPL thickness (standardized mean difference [SMD], -0.46; 95% confidence interval [CI], -0.80 to -0.11; IOur results confirmed the associations between retinal measurements of SD OCT and AD, highlighting the potential usefulness of SD OCT measurements as biomarkers of AD.

Purpose To determine whether Low Luminance Questionnaire (LLQ) scores are associated with objective measures of visual function in early and intermediate age-related macular degeneration (AMD). Methods Cross-sectional study of subjects with early AMD Age-Related Eye Disease Study (AREDS) stage 2, N = 33), intermediate AMD (AREDS stage 3, N = 47), and age-matched healthy controls (N = 21). Subjects were interviewed with the LLQ. Psychophysical tests performed included best-corrected visual acuity (BCVA), mesopic microperimetry, dark adaptometry (DA), low luminance visual acuity (LLVA), and cone contrast test (CCT). Low luminance deficit (LLD) was the difference in the number of letters read under photopic versus low luminance settings. The relationship between LLQ and visual function test scores was assessed with linear regression. Results Subjects with intermediate AMD had significantly lower LLQ composite scores (mean = 75.8 ± 16.7; median = 76, range [29, 97]) compared with early AMD (mean = 85.3 ± 13.3; median = 88, range [50, 100], P = 0.007) or controls (mean = 91.4 ± 6.5; median = 94, range [79, 99], P < 0.001) in the overall cohort. LLQ composite scores were associated with computerized BCVA (β = 0.516), computerized LLVA at two background luminance (1.3 cd/m2, β = 0.660; 0.5 cd/m2, β = 0.489) along with their respective computerized LLDs (β = -0.531 and -0.467), rod intercept (β = -0.312), and CCT green (β = 0.183) (all P < 0.05). Only the computerized LLVAs and computerized LLDs remained statistically significant after adjusting for AMD versus control status (P < 0.05). Among AMD subjects, LLQ composite scores were significantly associated with the computerized LLVAs (β = 0.622 and 0.441) and LLDs (β = -0.795 and -0.477) at both the 1.3 and 0.5 cd/m2 luminance levels, respectively, and these associations remained significant after adjusting for AMD severity (P < 0.05). Conclusions Among subjects with early and intermediate AMD, LLQ scores were significantly associated with computerized LLVA and LLD. LLQ is a useful patient-centered functional measure of visual impairment in early and intermediate AMD.

Despite increased rates of disease, disability, and social losses with aging, seniors consistently report higher levels of subjective well-being (SWB), a construct closely related to happiness, than younger adults. In this exploratory study, we utilized an available dataset to investigate how aspects of health commonly deteriorating with age, including sensory (i.e., vision and hearing) and cognitive status, relate to variability in self-described contributors to happiness. Community-dwelling seniors (n = 114) responded to a single-item prompt: “name things that make people happy.” 1731 responses were categorized into 13 domains of SWB via structured content analysis. Sensory health and cognition were assessed by Snellen visual acuity, pure-tone audiometry, and in-person administration of the Brief Test of Adult Cognition by Telephone (BTACT) battery. A subset of eligible participants (n = 57) underwent functional magnetic resonance imaging (fMRI) to assess resting state functional connectivity (FC) within a previously described dopaminergic network associated with reward processing. SWB response patterns were relatively stable across gender, sensory status, and cognitive performance with few exceptions. For example, hearing-impaired participants listed fewer determinants of SWB (13.59 vs. 17.16; p<0.001) and were less likely to name things in the “special events” category. Participants with a higher proportion of responses in the “accomplishments” domain (e.g., winning, getting good grades) demonstrated increased FC between the ventral tegmental area and nucleus accumbens, regions implicated in reward and motivated behavior. While the framework for determinants of happiness among seniors was largely stable across the factors assessed here, our findings suggest that subtle changes in this construct may be linked to sensory loss. The possibility that perceptions about determinants of happiness might relate to differences in intrinsic connectivity within reward-related brain networks also warrants further investigation.

Age-related macular degeneration (AMD), the leading cause of blindness in developed nations, has been associated with poor performance on tests of phonemic fluency. This pilot study sought to (1) characterize the relationship between phonemic fluency and resting-state functional brain connectivity in AMD patients and (2) determine whether regional connections associated with phonemic fluency in AMD patients were similarly linked to phonemic fluency in healthy participants. Behavior-based connectivity analysis was applied to resting-state, functional magnetic resonance imaging data from seven patients (mean age=79.9±7.5 years) with bilateral AMD who completed fluency tasks prior to imaging. Phonemic fluency was inversely related to the strength of functional connectivity (FC) among six pairs of brain regions, representing eight nodes: left opercular portion of inferior frontal gyrus (which includes Broca's area), left superior temporal gyrus (which includes part of Wernicke's area), inferior parietal lobe (bilaterally), right superior parietal lobe, right supramarginal gyrus, right supplementary motor area, and right precentral gyrus. The FC of these reference links was not related to phonemic fluency among 32 healthy individuals (16 younger adults, mean age=23.5±4.6 years and 16 older adults, mean age=68.3±3.4 years). Compared with healthy individuals, AMD patients exhibited higher mean connectivity within the reference links and within the default mode network, possibly reflecting compensatory changes to support performance in the setting of reduced vision. These findings are consistent with the hypothesis that phonemic fluency deficits in AMD reflect underlying brain changes that develop in the context of AMD.

Purpose To evaluate and quantify visual function metrics to be used as endpoints of AMD stages and visual acuity (VA) loss in patients with early and intermediate AMD. Design Cross-sectional analysis of baseline data from a prospective study. Methods 101 patients were enrolled at Duke Eye Center: 80 patients with early AMD age-related eye disease study (AREDS) stage 2 (N=33) and intermediate stage 3 (N=47) and 21 age-matched, normal controls. A dilated retinal examination, macular pigment optical density measurements, and several functional assessments: best-corrected VA, MAIA mesopic microperimety, dark adaptometry, low luminance VA (LLVA) (standard using a log 2.0 neutral density filter and computerized method) and cone contrast test (CCT) were performed. Low luminance deficit (LLD) was defined as the difference in numbers of letters read at standard vs. low luminance. Group comparisons were performed to evaluate differences between the control and the early and intermediate AMD groups using two-sided significance tests. Results Functional measures that significantly distinguished between normal and intermediate AMD were standard and computerized (0.5 cd/m 2 ) LLVA, percent reduced threshold and average threshold on microperimetry, CCTs, and rod intercept on dark adaptation (p Conclusions and Relevance: Our study suggests that LLVA, microperimetry, CCT and dark adaptation may serve as functional measures differentiating early-intermediate stages of dry AMD.

PURPOSE: Prior research in animal models has shown that macrophages and microglia play an important role in pathogenesis of glaucoma, but the phenotype and distribution of macrophages in human glaucomatous tissue have not been sufficiently characterized. METHODS: We analyzed H&E, CD68- and CD163-immunostained slides from 25 formaldehyde-fixed, paraffin-embedded autopsy eyes: 12 control eyes and 13 eyes with glaucoma. The diagnosis of glaucoma was made based on a history of glaucoma as reported in the medical record and histological changes characteristic of glaucoma. Glaucoma cases and controls were matched in terms of age, sex, and race. RESULTS: Qualitative analysis of the conventional outflow pathway and the optic nerve revealed that all eyes contained CD163+ cells but a negligible number of CD68+ cells. CD163+ macrophages infiltrated the trabecular meshwork and surrounded Schlemm’s canal of normal eyes and eyes with glaucoma, but the pattern was variable and qualitatively similar between groups. In optic nerves of control eyes, CD163+ macrophages were present at low levels and restricted to septa between axon bundles. In glaucomatous optic nerves, the number of CD163+ cells was increased both qualitatively and quantitatively (glaucoma 5.1 +/− 0.6 CD163+ cells/mm(2), control 2.5 +/− 0.3 CD163+ cells/mm(2), p < 0.001), with CD163+ cells infiltrating axon bundles in cases of both mild and severe disease. CONCLUSIONS: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.