Purpose: To examine whether ultra-widefield (UWF) retinal imaging can identify biomarkers for Alzheimer’s disease (AD) and its progression. Methods: Images were taken using a UWF scanning laser ...ophthalmoscope (Optos P200C AF) to determine phenotypic variations in 59 patients with AD and 48 healthy controls at baseline (BL). All living participants were invited for a follow-up (FU) after 2 years and imaged again (if still able to participate). All participants had blood taken for genotyping at BL. Images were graded for the prevalence of age-related macular degeneration-like pathologies and retinal vascular parameters. Comparison between AD patients and controls was made using the Student t test and the χ2 test. Results: Analysis at BL revealed a significantly higher prevalence of a hard drusen phenotype in the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%) χ2 = 9.9, df = 4, p = 0.04. A markedly increased drusen number was observed at the 2-year FU in patients with AD compared to controls. There was a significant increase in venular width gradient at BL (zone C: 8.425 × 10–3 ± 2.865 × 10–3 vs. 6.375 × 10–3 ± 1.532 × 10–3, p = 0.008; entire image: 8.235 × 10–3 ± 2.839 × 10–3 vs. 6.050 × 10–3 ± 1.414 × 10–3, p = 0.004) and a significant decrease in arterial fractal dimension in AD at BL (entire image: 1.250 ± 0.086 vs. 1.304 ± 0.089, p = 0.049) with a trend for both at FU. Conclusions: UWF retinal imaging revealed a significant association between AD and peripheral hard drusen formation and changes to the vasculature beyond the posterior pole, at BL and after clinical progression over 2 years, suggesting that monitoring pathological changes in the peripheral retina might become a valuable tool in AD monitoring.
Fundus autofluorescence (FAF) imaging is a novel imaging method that allows topographic mapping of lipofuscin distribution in the retinal pigment epithelium cell monolayer as well as of other ...fluorophores that may occur with disease in the outer retina and the subneurosensory space. Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases, including age-related macular degeneration. FAF imaging has been shown to be useful with regard to understanding of pathophysiologic mechanisms, diagnostics, phenotype-genotype correlation, identification of predictive markers for disease progression, and monitoring of novel therapies. FAF imaging gives information above and beyond that obtained by conventional imaging methods, such as fundus photography, fluorescein angiography, and optical coherence tomography. Its clinical value coupled with its simple, efficient, and noninvasive nature is increasingly appreciated. This review summarizes basic principles and FAF findings in various retinal diseases.
Significance Proteins and lipids accumulating in deposits external to the retinal pigment epithelium (RPE) represent a barrier to metabolic exchange between the retina and the choroidal capillaries. ...With time, these deposits can lead to age-related macular degeneration (AMD), the most common cause of blindness in the elderly in the developed world. It remains unclear how sub-RPE deposits are initiated and grow to clinically relevant features. Using a combination of high-resolution analytical techniques, we found that tiny hydroxyapatite (bone mineral) spherules with cholesterol-containing cores are present in all examined sub-RPE deposits, providing a scaffold to which proteins adhere. If the spherules are important in initiating sub-RPE deposit formation, this finding may provide attractive new approaches for early identification and treatment of AMD.
Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5–20 μm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch’s membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch’s membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits.
Age-related macular disease (AMD) is a major cause of blindness and there is little treatment currently available by which the progress of the basic disorder can be modulated. Histological and ...clinical studies show that the major tissues involved are the outer retina, retinal pigment epithelium, Bruch's membrane and choroid. Because of a wide variation of phenotype from one case to another, it has been suggested that accurate phenotyping would be necessary for assessment of the effectiveness of treatment that is tissue-directed. However, based on findings from the study of human donor material and animal models of disease and of cell culture, it is concluded that retinal pigment epithelial dysfunction plays a central role in the disease process in most, if not all, cases of early AMD. The metabolism of phagosomal material, particularly lipids, and energy generation are interdependent, and dysfunction of both appears to be important in the genesis of disease. Evidence exists to suggest that both can be modulated therapeutically. These metabolic functions are amenable to further investigation in both the normal state and in disease. Once fully characterised, it is likely that treatment could be directed towards a limited number of functions in single tissue, thus simplifying treatment strategies.
A very recent report identified the interaction between the receptor-binding domain of the spike glycoprotein (S protein) of SARS-CoV-2 and the peptidase domain of angiotensin-converting enzyme 2 ...(ACE2) as critical for viral entry into host cells.1 Because of the strong link between ACE2 and SARS-CoV-2 infection, inhibitors of ACE2 have been discussed as potential therapeutic agents against COVID-19.2,3 We believe there already might be a safe, potential inhibitor of ACE2 function that could constrain the ability of SARS-CoV-2 to infect cells—and that is the trace mineral zinc. Research at that time identified interaction between the S protein of SARS-CoV and ACE2 as a mechanism of viral infection.4 ACE2 is a type I integral membrane protein characterized by the HEXXH + E zinc-binding domain and is found on the surface of epithelial cells of the heart, lung, kidney, and intestine. In view of the serious, life-threatening circumstances of this pandemic, we believe there is potential benefit in taking oral zinc for those at risk of developing COVID-19. ...shorter open-label retrospective studies should be quickly completed.
To investigate progressive vision loss in patients with macular telangiectasia (MacTel) type 2 and to compare the ability to detect functional decline between microperimetry and visual acuity ...testing.
Change of cumulative defect size (number of test points with absolute scotoma) on microperimetry testing and change in distance best-corrected visual acuity (BCVA) were evaluated in a prospective longitudinal observational study.
The mean review period was 55.3 months (SD 17.3 months). In 58% of 71 eyes (40 patients) included for analysis, microperimetry revealed spread (n = 31) or new development (n = 10) of an absolute scotoma. At the same time, BCVA decreased more than two lines in only 17% (n = 12). Twenty-five (35%) eyes showed no change in visual function. Presence of an absolute scotoma at baseline, but not baseline BCVA, was predictive for functional decline on longitudinal microperimetry testing. Eyes with an absolute scotoma at baseline (n = 33) showed further growth of the scotoma in 94% (n = 31). In contrast, only 26% (n = 10) of eyes without an absolute scotoma at baseline (n = 38) developed an absolute scotoma de novo. Scotoma growth rate (new test points with an absolute scotoma per year) was 0.62 ± 0.10 for all eyes and 1.30 ± 0.12 for the subgroup of eyes with scotoma at baseline. Scotomata always first occurred in the quadrant temporal to the foveal center.
A characteristic feature in patients with MacTel type 2 is progressive focal loss of macular sensitivity, preceding loss of visual acuity. Microperimetry is sensitive to detect such functional decline and thus may provide considerable power when being used as a functional outcome measure in future clinical trials.
Abstract Drusen have been considered the clinical hallmark of age-related macular degeneration (AMD). Reticular pseudodrusen (RPD), although first described about 25 years ago, have only been ...recently recognized as an additional clinical phenotype of AMD with distinct characteristics on multimodal imaging and significant impact on visual function. Eyes with RPD are at greater risk of progression to advanced AMD when compared with eyes with drusen only. RPD can also occur in the absence of drusen. Unlike features external to the retinal pigment epithelium that have received most attention in AMD, evidence suggests that RPD are associated with changes internal to the RPE. Therefore, new avenues regarding the pathogenesis of AMD are highlighted by these recent observations. We summarize the current knowledge regarding the histology, imaging, and functional changes in eyes with RPD in AMD and offer concepts of future research for the AMD community to discuss.
Purpose To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. ...Design An open-label safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. Methods The participant's more severely affected eye (worse baseline visual acuity) received the high-dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. Results The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. Conclusions The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy.
To review the epidemiology of age-related macular degeneration (AMD).
Evidence from epidemiologic data regarding the natural history of AMD and its risk factors are presented.
Large, soft drusen ...associated with pigmentary abnormalities increase the risk of progression to advanced AMD. Large soft drusen may fade over time. Advanced AMD is more likely to be present in whites than blacks, despite the similar prevalence of soft drusen in both groups. Neovascular AMD is more frequent than geographic atrophy in most population-based studies in whites in America, Australia, and the Netherlands than in similar population-based studies in Iceland and Norway. After age and family history, there are few consistent relationships of risk factors to AMD. Of these, the relationship of smoking, hypertension, and cataract surgery to advanced AMD have been most consistent.
Long-term epidemiologic studies have provided information on the distribution and the natural history of AMD and its associated risk factors. It is not known what effect reduction of blood pressure and the cessation of smoking might have on the incidence and progression of AMD.
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