350 results on '"Curcio, CA"'
Search Results
2. Intrazelluläre Granulaverteilung des menschlichen retinalen Pigmentepithels (RPE) bei der altersabhängigen Makuladegeneration (AMD): Basis verminderter klinischer Autofluoreszenz
- Author
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Emde, Lvd, Bermond, K, Bourauel, L, Sloan, KR, Curcio, CA, Heintzmann, R, Holz, FG, Ach, T, Emde, Lvd, Bermond, K, Bourauel, L, Sloan, KR, Curcio, CA, Heintzmann, R, Holz, FG, and Ach, T
- Published
- 2022
Catalog
3. Fluoreszenzlebensdauer-Ophthalmoskopie (FLIO) von RPE-Veränderungen bei AMD in vivo und ex vivo
- Author
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Schultz, R, Jentsch, M, Jakob-Girbig, J, Schwanengel, L, Curcio, CA, Hasan, S, Meller, D, and Hammer, M
- Subjects
ddc: 610 ,Medicine and health - Abstract
Hintergrund: Sichtbare Veränderungen des retinalen Pigmentepithels (RPE) in der Farbfundusfotografie (CFP) und optische Kohärenztomografie (OCT) bei AMD sind ein Risikofaktor für die Krankheitsprogression hin zur geographischen Atrophie (GA). Der am besten untersuchte Weg beinhaltet die [zum vollständigen Text gelangen Sie über die oben angegebene URL] more...
- Published
- 2021
- Full Text
- View/download PDF
4. Multiscale clinicopathologic correlation of canonical and non-canonical intraretinal neovascularization in age-related macular degeneration (AMD)
- Author
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Messinger, Jd, Chen, L, Berlin, A, Kar, D, Bacci, T, Balaratnasingham, C, Mendes, R, Ferrara, D, Freund, Kb, and Curcio, Ca
- Published
- 2021
5. Histology and clinical lifecycle of acquired vitelliform lesion, a pathway to atrophy in age-related macular degeneration
- Author
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Brinkmann, Mp, Bacci, T, Messinger, J, Kar, D, Sloan, Kr, Chen, L, Hamann, T, Wiest, M, Freund, Kb, Zweifel, Sa, and Curcio, Ca
- Published
- 2021
6. Molecular microarchitecture of macula in health and AMD
- Author
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Curcio, CA, Kar, D, Dacey, DM, Anderson, DMG, Kotnala, A, and Schey, KL
- Subjects
ddc: 610 ,genetic structures ,sense organs ,610 Medical sciences ,Medicine ,eye diseases - Abstract
Background: In normal human macula, we investigated with comprehensive molecular and ultrastructural technologies an ecosystem that contributes to drusen lipids (PMID 30357337). Two features of high-risk drusen and their precursors in Bruch’s membrane implicate macular biology: enrichment in [for full text, please go to the a.m. URL], 7th International Symposium on AMD: Age-related Macular Degeneration - Understanding Pathogenetic Mechanisms of Disease more...
- Published
- 2020
- Full Text
- View/download PDF
7. Cellular and subcellular changes in the RPE: from normal aging to early signs of AMD
- Author
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Ach, T, Bermond, K, Gambril, JA, Wobbe, C, Berlin, A, Heintzmann, R, Sloan, KR, Curcio, CA, Ach, T, Bermond, K, Gambril, JA, Wobbe, C, Berlin, A, Heintzmann, R, Sloan, KR, and Curcio, CA
- Published
- 2020
8. Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration Classification of Atrophy Meeting Report 4
- Author
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Guymer, RH, Rosenfeld, PJ, Curcio, CA, Holz, FG, Staurenghi, G, Freund, KB, Schmitz-Valckenberg, S, Sparrow, J, Spaide, RF, Tufail, A, Chakravarthy, U, Jaffe, GJ, Csaky, K, Sarraf, D, Mones, JM, Tadayoni, R, Grunwald, J, Bottoni, F, Liakopoulos, S, Pauleikhoff, D, Pagliarini, S, Chew, EY, Viola, F, Fleckenstein, M, Blodi, BA, Lim, TH, Chong, V, Lutty, J, Bird, AC, Sadda, SR, Guymer, RH, Rosenfeld, PJ, Curcio, CA, Holz, FG, Staurenghi, G, Freund, KB, Schmitz-Valckenberg, S, Sparrow, J, Spaide, RF, Tufail, A, Chakravarthy, U, Jaffe, GJ, Csaky, K, Sarraf, D, Mones, JM, Tadayoni, R, Grunwald, J, Bottoni, F, Liakopoulos, S, Pauleikhoff, D, Pagliarini, S, Chew, EY, Viola, F, Fleckenstein, M, Blodi, BA, Lim, TH, Chong, V, Lutty, J, Bird, AC, and Sadda, SR more...
- Abstract
PURPOSE: To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. DESIGN: Consensus meeting. PARTICIPANTS: Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. METHODS: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. MAIN OUTCOME MEASURES: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. RESULTS: OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. CONCLUSIONS: An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventi more...
- Published
- 2020
9. The association between statin use and age related maculopathy
- Author
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McGwin, Jr, G, Owsley, C, Curcio, CA, and Crain, RJ
- Subjects
Macular degeneration -- Research -- Causes of ,Health ,Research ,Causes of - Abstract
Aims: To evaluate the association between age related maculopathy (ARM) and statin use. Methods: A nested case-control study among patients at the Veterans Affairs Medical Center in Birmingham, Alabama, with [...] more...
- Published
- 2003
10. Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration
- Author
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Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM more...
- Abstract
PURPOSE: Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. METHODS: We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. RESULTS: We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) "drive" the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. CONCLUSIONS: We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD. more...
- Published
- 2019
11. Clinical and nano-analytical imaging identify calcified nodules as progression markers for age-related macular degeneration
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Tan, ACS, Pilgrim, M, Fearn, S, Bertazzo, S, Tsolaki, E, Morrell, AP, Li, M, Messinger, J, Dolz-Marco, R, Lei, J, Nittala, MG, Sadda, SR, Lengyel, I, Freund, KB, and Curcio, CA
- Subjects
Ophthalmology ,Science & Technology ,11 Medical And Health Sciences ,06 Biological Sciences ,Ophthalmology & Optometry ,Life Sciences & Biomedicine - Published
- 2018
12. Clinicopathologic Correlation of Anti-Vascular Endothelial Growth Factore-Treated Type 3 Neovascularization in Age-Related Macular Degeneration
- Author
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Li M, Dolz-Marco R, Messinger JD, Wang L, Feist RM, Girkin CA, Gattoussi S, Ferrara D, Curcio CA, and Freund KB
- Subjects
genetic structures ,sense organs ,eye diseases - Abstract
Purpose: To correlate histologic results with previously recorded multimodal imaging results from a patient with type 3 neovascularization secondary to age-related macular degeneration (AMD). Design: Case study, clinical imaging, laboratory imaging, and eye-tracked clinicopathologic correlation. Participant: An 86-year-old white woman with type 3 neovascularization secondary to AMD treated with 6 intravitreal injections of bevacizumab. Methods: Multimodal retinal imaging at each clinic visit was correlated with ex vivo and high-resolution histologic images of the preserved donor eye. Clinical imaging included serial near-infrared reflectance and eye-tracked spectral-domain OCT. Eye tracking, applied to the donor eye, enabled identification of histologic features corresponding to clinical OCT signatures. Main Outcome Measures: Histologic correlates for clinical OCT signatures were sought, including reflectivity of the vascular complex, intraretinal hyperreflective foci and intraretinal cellularity, analysis of the topography of pathologic features, and evaluation of the suberetinal pigment epithelium (RPE) plus basal lamina (BL) space. Results: Clinical imaging showed a deep neovascular lesion in close relationship with a mixed serous and drusenoid pigment epithelium detachment (PED), characteristic of type 3 neovascularization. Antiangiogenic therapy achieved a complete resolution of exudation. The PED progressively flattened with each treatment, leaving a persistent triangular hyperreflectivity in the outer retina. This persistent deep lesion histologically correlated with a vascular complex implanted into sub-RPE basal laminar deposit. No connection between the choriocapillaris and the sub-RPE plus BL space was observed. Both RPE-derived and lipid-filled cells were correlated with clinical intraretinal hyperreflective foci. The sub-RPE plus BL space contained macrophages, lymphocytes, Muller cell processes, and subducted RPE. Conclusions: Clinicopathologic correlation of type 3 neovascularization showed vascular elements of retinal origin accompanied by collagenous material and Muller cell processes implanting into thick sub-RPE basal laminar deposit, which may simulate the appearance of chorioretinal anastomosis. Surrounding RPEderived and lipid-filled cells thought to be microglia correlated with clinical intraretinal hyperreflective foci. (C) 2017 by the American Academy of Ophthalmology more...
- Published
- 2018
13. Choroidal and Sub-Retinal Pigment Epithelium Caverns Multimodal Imaging and Correspondence with Friedman Lipid Globules
- Author
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Dolz-Marco R, Glover JP, Gal-Or O, Litts KM, Messinger JD, Zhang Y, Cozzi M, Pellegrini M, Freund KB, Staurenghi G, and Curcio CA
- Subjects
genetic structures ,sense organs ,eye diseases - Abstract
Purpose: To survey Friedman lipid globules by high-resolution histologic examination and to compare with multimodal imaging of hyporeflective caverns in eyes with geographic atrophy (GA) secondary to age-related macular (AMD) and other retinal diseases. Design: Histologic survey of donor eyes with and without AMD. Clinical case series with multimodal imaging analysis. Participants: Donor eyes (n = 139; 26 with early AMD, 13 with GA, 40 with nAMD, 52 with a healthy macula, and 8 with other or unknown characteristics) and 41 eyes of 28 participants with GA (n = 16), nAMD (n = 8), Stargardt disease (n = 4), cone dystrophy (n = 2), pachychoroid spectrum (n = 6), choroidal hemangioma (n = 1), and healthy eyes (n = 4). Methods: Donor eyes were prepared for macula-wide epoxy resin sections through the foveal and perifoveal area. In patients, caverns were identified as nonreflective spaces on OCT images. Multimodal imaging included color and red-free fundus photography; fundus autofluorescence; fluorescein and, indocyanine green angiography; OCT angiography; near-infrared reflectance; and confocal multispectral (MultiColor [Spectralis, Heidelberg Engineering, Germany]) imaging. Main Outcome Measures: Presence and morphologic features of globules, and presence and appearance of caverns on multimodal imaging. Results: Globules were found primarily in the inner choroidal stroma (91.0%), but also localized to the sclera (4.9%) and neovascular membranes (2.1%). Mean diameters of solitary and multilobular globules were 58.9 +/- 37.8 mu m and 65.4 +/- 27.9 mu m, respectively. Globules showed morphologic signs of dynamism including pitting, dispersion, disintegration, and crystal formation. Evidence for inflammation in the surrounding tissue was absent. En face OCT rendered sharply delimited hyporeflective areas as large as choroidal vessels, frequently grouped around choroid vessels or in the neovascular tissue. Cross-sectional OCT revealed a characteristic posterior hypertransmission. OCT angiography showed absence of flow signal within caverns. Conclusions: Based on prior literature documenting OCT signatures of tissue lipid in atheroma and nAMD, we speculate that caverns are lipid rich. Globules, with similar sizes and tissue locations in AMD and healthy persons, are candidates for histologic correlates of caverns. The role of globules in chorioretinal physiologic features, perhaps as a lipid depot for photoreceptor metabolism, is approachable through clinical imaging. (C) 2018 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology more...
- Published
- 2018
14. Imaging protocols in clinical studies in advanced age-related macular degeneration: recommendations from classification of atrophy consensus meetings
- Author
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Holz, FG, Sadda, SR, Staurenghi, G, Lindner, M, Bird, AC, Blodi, BA, Bottoni, F, Chakravarthy, U, Chew, EY, Csaky, K, Curcio, CA, Danis, R, Fleckenstein, M, Freund, KB, Grunwald, J, Guymer, R, Hoyng, CB, Jaffe, GJ, Liakopoulos, S, Monés, JM, Oishi, A, Pauleikhoff, D, Rosenfeld, PJ, Sarraf, D, Spaide, RF, Tadayoni, R, Tufail, A, Wolf, S, Schmitz-Valckenberg, S, and CAM group more...
- Subjects
genetic structures ,sense organs ,eye diseases - Abstract
PURPOSE: To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN: Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS: A panel of retina specialists. METHODS: During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES: Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS: Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. CONCLUSIONS: A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future. more...
- Published
- 2017
- Full Text
- View/download PDF
15. The Evolution of Outer Retinal Tubulation, a Neurodegeneration and Gliosis Prominent in Macular Diseases
- Author
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Dolz-Marco, R, Litts, KM, Tan ACS, Freund, KB, and Curcio, CA
- Subjects
genetic structures ,sense organs ,eye diseases - Abstract
Purpose: To document outer retinal tubulation (ORT) formation in advanced retinal disorders. Design: Retrospective, observational study. Participants: Consecutive cases with retinal diseases showing outer retinal disruption and atrophy of the retinal pigment epithelium (RPE) associated with ORT on spectral-domain (SD) optical coherence tomography (OCT) at the final available visit. Methods: Cross-sectional SD OCT scans showing ORT at the last available visit were compared with eye-tracked baseline scans. Only patients showing the formation of ORT over time with absence of ORT at baseline were analyzed. Main Outcome Measures: Steps in ORT formation based on shapes of the external limiting membrane (ELM) descent (flat, curved, reflected, and scrolled) at the border of outer retinal and RPE atrophy, ORT characteristics (open, closed), and time between steps through a long-term follow-up. Results: From 170 eyes of 86 patients with ORT, 38 eyes of 30 patients (11 men, 19 women) with a mean age of 78.87 years (range, 56-96 years) met inclusion criteria. Of these 38 eyes, 23 (60%) had geographic atrophy secondary to age-related macular degeneration (AMD) and 2 eyes (5%) had geographic atrophy secondary to pattern dystrophy. Twelve eyes (32%) had neovascular AMD and 1 eye (3%) had neovascularization secondary to pseudoxanthoma elasticum, all showing similar ORT formative steps. Seventy-three different retinal areas (1434 cross-sectional images) were analyzed over a mean follow-up of 69.5 months (range, 21-93 months). At 73 borders, grading of eye-tracked follow-up SD OCT line scans showed a flat ELM descent at least once at 34 borders (47%), a curved ELM at 47 borders (64%), a reflected ELM at 37 borders (51%), and a scrolled ELM at 24 borders (33%). Of 81 ORTs, 73 (90%) were closed and 8 (10%) were open. The mean time for ORT formation was 14.9 months (range, 1.4-71.3 months). Conclusions: We propose progressive steps in the development of ORT and analyze the time of progression between these steps. Analyzing the borders of atrophy to determine the origin of ORT provides new insights into the pathophysiology of advanced retinal disease highlighting a role for Muller cells and may inform future therapeutic strategies. (C) 2017 by the American Academy of Ophthalmology more...
- Published
- 2017
16. Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration
- Author
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Holz, FG, Sadda, SR, Staurenghi, G, Lindner, M, Bird, AC, Blodi, BA, Bottoni, F, Chakravarthy, U, Chew, EY, Csaky, K, Curcio, CA, Danis, R, Fleckenstein, M, Freund, KB, Grunwald, J, Guymer, R, Hoyng, CB, Jaffe, GJ, Liakopoulos, S, Mones, JM, Oishi, A, Pauleikhoff, D, Rosenfeld, PJ, Sarraf, D, Spaide, RF, Tadayoni, R, Tufail, A, Wolf, S, Schmitz-Valckenberg, S, Holz, FG, Sadda, SR, Staurenghi, G, Lindner, M, Bird, AC, Blodi, BA, Bottoni, F, Chakravarthy, U, Chew, EY, Csaky, K, Curcio, CA, Danis, R, Fleckenstein, M, Freund, KB, Grunwald, J, Guymer, R, Hoyng, CB, Jaffe, GJ, Liakopoulos, S, Mones, JM, Oishi, A, Pauleikhoff, D, Rosenfeld, PJ, Sarraf, D, Spaide, RF, Tadayoni, R, Tufail, A, Wolf, S, and Schmitz-Valckenberg, S more...
- Abstract
PURPOSE: To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN: Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS: A panel of retina specialists. METHODS: During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES: Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS: Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain more...
- Published
- 2017
17. Hochaufgelöste Darstellung autofluoreszierender Granula von RPE-Zellen: Grundlage für detaillierte intrazelluläre Analysen
- Author
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Ach, T, Hong, S, Heintzmann, R, Hillenkamp, J, Curcio, CA, Gerig, G, Bermond, K, Ach, T, Hong, S, Heintzmann, R, Hillenkamp, J, Curcio, CA, Gerig, G, and Bermond, K
- Published
- 2017
18. A primary retinal pigment epithelial (RPE) cell culture model produces lipid- and hydroxyapatite-rich extracellular deposits characteristic of early stage age-related macular degeneration
- Author
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Pilgrim, MG, Lanzirotti, A, Newville, M, Fearn, S, Knowles, J, Messinger, JD, Read, RW, Guidry, C, Curcio, CA, and Lengyel, I
- Subjects
Ophthalmology ,Science & Technology ,11 Medical And Health Sciences ,06 Biological Sciences ,Ophthalmology & Optometry ,Life Sciences & Biomedicine - Published
- 2016
19. Intraretinal Hyperreflective Foci in Acquired Vitelliform Lesions of the Macula: Clinical and Histologic Study
- Author
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Chen, KC, Jung, JJ, Curcio, CA, Balaratnasingam, C, Gallego-Pinazo, R, Dolz-Marco, R, Freund, KB, and Yannuzzi, LA
- Subjects
genetic structures ,sense organs ,eye diseases - Abstract
PURPOSE: To describe the natural course, visual outcomes, and anatomic changes and provide histologic correlates in eyes with intraretinal hyperreflective foci associated with acquired vitelliform lesions. DESIGN: Retrospective cohort study and imaging histology correlation in a single donor eye. METHODS: PARTICIPANTS: Patients with intraretinal hyperreflective foci and acquired vitelliform lesions from 2 tertiary referral centers were evaluated from January 2002 to January 2014. MAIN OUTCOME MEASURES: The chronology of clinical and imaging features of retinal anatomic changes and the pattern of intraretinal hyperreflective foci migration were documented using spectral-domain optical coherence tomography (OCT). One donor eye with intraretinal hyperreflective foci was identified in a pathology archive by ex vivo OCT and was studied with high resolution light and electron microscopic examination. RESULTS: Intraretinal hyperreflective foci were associated with acquired vitelliform lesions in 25 of 254 eyes (9.8%) with a strong female preponderance (86% of patients). Focal disruptions to the ellipsoid zone and external limiting membrane overlying the acquired vitelliform lesions were observed prior to the occurrence of intraretinal hyperreflective foci in 75% of cases. Histologic evaluation showed that intraretinal hyperreflective foci represent cells of retinal pigment epithelium origin that are similar to those found in the vitelliform lesions themselves and contain lipofuscin granules, melanolipofuscin granules, and melanosomes. The occurrence of intraretinal hyperreflective foci was not a significant determinant of final visual acuity (P = .34), but development of outer retinal atrophy was (P = .003). CONCLUSIONS: Intraretinal hyperreflective foci associated with acquired vitelliform lesions are of retinal pigment epithelium origin, and the natural course and functional changes are described. (C) 2016 by Elsevier Inc. All rights reserved. more...
- Published
- 2016
20. The impact of subretinal drusenoid deposits (SDD) on surrounding photoreceptors revealed by multimodal imaging and mesopic and scotopic microperimetry
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Zhang, Y, Wang, X, Clark, M, Owsley, C, and Curcio, CA
- Subjects
ddc: 610 ,genetic structures ,sense organs ,610 Medical sciences ,Medicine ,eye diseases - Abstract
Background: Drusen are extracellular lesions in the sub-RPE (retinal pigment epithelium) space, a hallmark of age-related macular degeneration (AMD). SDD are solid space-filling lesions in the subretinal space that confer risk for AMD progression independent of drusen. We assess the impact of drusen[for full text, please go to the a.m. URL], VI. International Symposium on AMD – Age-Related Macular Degeneration – Emerging Concepts – Exploring known and Identifying new Pathways more...
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- 2015
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21. Visualizing RPE fate in AMD with histology and optical coherence tomography
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Curcio, CA
- Subjects
ddc: 610 ,sense organs ,610 Medical sciences ,Medicine ,eye diseases - Abstract
The compartmentalization of light scattering organelles in photoreceptors and retinal pigment epithelium (RPE) makes it possible to assign the four outer retinal hyperreflective bands of spectral domain optical coherence tomography (SDOCT) to specific subcellular sources. Histological analysis of short[for full text, please go to the a.m. URL], VI. International Symposium on AMD – Age-Related Macular Degeneration – Emerging Concepts – Exploring known and Identifying new Pathways more...
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- 2015
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22. As the bright light dims: loss of lipofuscin-attributable autofluorescence from RPE in aging and AMD
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Ach, T, Smith, RT, Ablonczy, Z, Hillenkamp, J, Heintzmann, R, Sloan, KR, and Curcio, CA
- Subjects
ddc: 610 ,genetic structures ,sense organs ,610 Medical sciences ,Medicine ,eye diseases - Abstract
Background: In healthy persons, fundus autofluorescence (AF) intensity diminishes after age 70 [ref:1], with the underlying mechanisms still unknown. In age-related macular degeneration (AMD), hypoautofluorescent areas in fundus AF-imaging are often referred to as retinal pigment epithelium[for full text, please go to the a.m. URL], VI. International Symposium on AMD – Age-Related Macular Degeneration – Emerging Concepts – Exploring known and Identifying new Pathways more...
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- 2015
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23. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
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Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM more...
- Abstract
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes. more...
- Published
- 2016
24. Quantitative Autofluoreszenz (AF)- und Zelldichte-Karten des humanen retinalen Pigmentepithels (RPE)
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Ach, T, Huisingh, C, McGwin, G, Messinger, JD, Zhang, T, Bentley, MJ, Gutierrez, DB, Ablonczy, Z, Smith, RT, Sloan, KR, Curcio, CA, Ach, T, Huisingh, C, McGwin, G, Messinger, JD, Zhang, T, Bentley, MJ, Gutierrez, DB, Ablonczy, Z, Smith, RT, Sloan, KR, and Curcio, CA more...
- Published
- 2014
25. Band Visibility in High-Resolution Optical Coherence Tomography Assessed With a Custom Review Tool and Updated, Histology-Derived Nomenclature.
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Goerdt L, Swain TA, Kar D, McGwin G, Berlin A, Clark ME, Owsley C, Sloan KR, and Curcio CA
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- Humans, Adult, Aged, Young Adult, Male, Female, Retina diagnostic imaging, Aged, 80 and over, Middle Aged, Reproducibility of Results, Tomography, Optical Coherence methods, Terminology as Topic, Macular Degeneration pathology, Macular Degeneration diagnostic imaging, Aging
- Abstract
Purpose: For structure-function research at the transition of aging to age-related macular degeneration, we refined the current consensus optical coherence tomography (OCT) nomenclature and evaluated a novel review software for investigational high-resolution OCT imaging (HR-OCT; <3 µm axial resolution)., Method: Volume electron microscopy, immunolocalizations, histology, and investigational devices informed a refined OCT nomenclature for a custom ImageJ-based review tool to assess retinal band visibility. We examined effects on retinal band visibility of automated real-time averaging (ART) 9 and 100 (11 eyes of 10 healthy young adults), aging (10 young vs 22 healthy aged), and age-related macular degeneration (AMD; 22 healthy aged, 17 early (e)AMD, 15 intermediate (i)AMD). Intrareader reliability was assessed., Results: Bands not included in consensus nomenclature are now visible using HR-OCT: inner plexiform layer (IPL) 1-5, outer plexiform layer (OPL) 1-2, outer segment interdigitation zone 1-2 (OSIZ, including hyporeflective outer segments), and retinal pigment epithelium (RPE) 1-5. Cohen's kappa was 0.54-0.88 for inner and 0.67-0.83 for outer retinal bands in a subset of 10 eyes. IPL-3-5 and OPL-2 visibility benefitted from increased ART. OSIZ-2 and RPE-1,2,3,5 visibility was worse in aged eyes than in young eyes. OSIZ-1-2, RPE-1, and RPE-5 visibility decreased in eAMD and iAMD compared to healthy aged eyes., Conclusions: We reliably identified 28 retinal bands using a novel review tool for HR-OCT. Image averaging improved inner retinal band visibility. Aging and AMD development impacted outer retinal band visibility., Translational Significance: Detailed knowledge of anatomic structures visible on OCT will enhance precision in research, including AI training and structure-function analyses. more...
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- 2024
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26. Abetalipoproteinemia with angioid streaks, choroidal neovascularization, atrophy, and extracellular deposits revealed by multimodal retinal imaging.
- Author
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Bijon J, Hussain MM, Bredefeld CL, Boesze-Battaglia K, Freund KB, and Curcio CA
- Subjects
- Humans, Female, Aged, Middle Aged, Fluorescein Angiography, Retinal Drusen genetics, Retinal Drusen diagnosis, Retinal Drusen pathology, Retinal Pigment Epithelium pathology, Atrophy, Bruch Membrane pathology, Choroidal Neovascularization genetics, Choroidal Neovascularization diagnosis, Choroidal Neovascularization pathology, Abetalipoproteinemia genetics, Abetalipoproteinemia diagnosis, Abetalipoproteinemia pathology, Tomography, Optical Coherence, Angioid Streaks genetics, Angioid Streaks diagnosis, Multimodal Imaging
- Abstract
Purpose: Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas., Methods: We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD)., Results: Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments., Conclusion: We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition. more...
- Published
- 2024
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27. A possible association between intraocular pressure changes and pigment epithelial detachment in central serous chorioretinopathy.
- Author
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Balaratnasingam C, Curcio CA, Morgan WH, and van Dijk EHC
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- Humans, Fluorescein Angiography methods, Male, Visual Acuity physiology, Female, Middle Aged, Adult, Bruch Membrane pathology, Central Serous Chorioretinopathy diagnosis, Central Serous Chorioretinopathy physiopathology, Central Serous Chorioretinopathy complications, Retinal Detachment diagnosis, Retinal Detachment etiology, Retinal Detachment physiopathology, Intraocular Pressure physiology, Tomography, Optical Coherence methods, Retinal Pigment Epithelium pathology
- Abstract
Central serous chorioretinopathy (CSC) is a frequently occurring chorioretinal disease, that is commonly associated with subretinal fluid accumulation in a generally young population. Even though choroidal abnormalities have been found to be of importance, the exact pathogenesis of CSC is still being learned. The origin of pigment epithelial detachments, seen in many CSC patients, is also unclear. Based on the follow-up of a CSC patient for more than 5 years, we hypothesize that intraocular pressure and, by extension, the pressure gradient across the Bruch's membrane, may be one factor in the pathogenesis of pigment epithelial detachments in CSC, which might very well have implications for the occurrence of and possible ways to prevent subretinal fluid in CSC., (© 2024 The Author(s). Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.) more...
- Published
- 2024
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28. Antiperspirant-related zirconium and aluminum-containing granulomas; histopathology and in situ chemical analysis.
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Sanford JA, Candelaria-Santiago R, Forte DM, Curcio CA, Allbritton JI, Strausborger SL, and Lewin-Smith MR
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- Humans, Female, Adult, Granuloma, Foreign-Body pathology, Granuloma, Foreign-Body chemically induced, Granuloma, Foreign-Body etiology, Axilla pathology, Zirconium adverse effects, Antiperspirants adverse effects, Aluminum adverse effects
- Abstract
The potential adverse health effects of antiperspirant use are of interest to patients, primary care providers, dermatologists, and pathologists. In rare instances, antiperspirants containing aluminum-zirconium complexes have been associated with granulomatous dermatoses despite being deemed non-sensitizing in experiments. In this case study, we present a detailed examination of an axillary granuloma in a 28-year-old female who had been using an aluminum-zirconium-based antiperspirant for several years and presented with a left axillary nodule that was excised and analyzed using scanning electron microscopy with energy-dispersive x-ray analysis (SEM/EDXA). Histopathological examination revealed a foreign body-type reaction with amphophilic granular material within giant cells that corresponded to collocated zirconium and aluminum on SEM/EDXA elemental maps. Our case adds to the limited reports of axillary granulomas related to aluminum-zirconium complexes. It illustrates the histopathological appearance and in situ distribution of the aluminum-zirconium complexes, supporting the formation of foreign body-type granulomas. Additionally, our case study illustrates the potential role of these compounds in such reactions and aims to increase awareness among pathologists and clinicians., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.) more...
- Published
- 2024
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29. Outer Retinal Thinning is Associated With Brain Atrophy in Early Age-Related Macular Degeneration.
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Jiang Y, Swain T, Gim N, Blazes M, Donald CM, Rokem A, Owen JP, Balu N, Clark ME, Goerdt L, McGwin G, Hunt D, Curcio CA, Levendovszky SR, Trittschuh EH, Owsley C, and Lee CS
- Subjects
- Humans, Female, Cross-Sectional Studies, Male, Aged, Aged, 80 and over, Brain pathology, Brain diagnostic imaging, Retina pathology, Retina diagnostic imaging, Macular Degeneration diagnosis, Tomography, Optical Coherence methods, Magnetic Resonance Imaging, Atrophy
- Abstract
Purpose: Both retinal changes and age-related macular degeneration (AMD) have been shown to be associated with Alzheimer's disease and related dementias (ADRD). In AMD, the outer retina is impacted significantly and early, but little is known about its association with cognition or changes in brain morphometry. This study investigates the relationship between retinal and brain morphometry in older adults with early and intermediate AMD., Design: Cross-sectional study., Methods: Adults ≥70 years with normal, early, and intermediate AMD were recruited from Callahan Eye Hospital Clinics at the University of Alabama at Birmingham. Participants underwent cognitive testing, optical coherence tomography, and magnetic resonance imaging. Associations of retinal layer thickness with brain volume and thickness of specific brain regions were evaluated utilizing multivariable linear regression. The relevance of retinal thickness variables in brain volumetrics was quantified using least absolute shrinkage and selection operator regression models. Correlations between demographic variables, cognitive scores, and brain morphometry were evaluated., Results: Participants with thinner outer retina had significantly smaller hippocampus (β = 0.019, P = .022), lower occipital cortex regions of interest (occipital ROIs) thickness (β = 5.68, P = .020), and lower cortical thickness in ADRD-related brain regions (β = 7.72, P = .006). People with thinner total retina had significantly lower occipital ROIs (β = 3.19, P = .009) and ADRD-related brain region (β = 3.94, P = .005) thickness. Outer retinal thickness in the outer Early Treatment of Diabetic Retinopathy Study ring was the most frequently reported retinal variable associated with brain morphometry on least absolute shrinkage and selection operator regression. Total gray matter volume showed positive correlations with education (Pearson's r = 0.30, P = .022)., Conclusions: In older adults with normal retinal aging and early and intermediate AMD, thinner outer retina had specific associations with brain regions primarily involved in vision and cognition, such as lower hippocampal volume and lower thickness of the occipital ROIs and brain regions known to show early structural changes in dementia., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...
- Published
- 2025
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30. Topographic Measurement of the Subretinal Pigment Epithelium Space in Normal Aging and Age-Related Macular Degeneration Using High-Resolution OCT.
- Author
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Won J, Takahashi H, Ploner SB, Karbole W, Abu-Qamar O, Yaghy A, Marmalidou A, Kaiser S, Hwang Y, Lin J, Witkin A, Desai S, Baumal CR, Maier A, Curcio CA, Waheed NK, and Fujimoto JG
- Subjects
- Humans, Aged, Middle Aged, Prospective Studies, Cross-Sectional Studies, Female, Male, Aged, 80 and over, Adult, Young Adult, Bruch Membrane pathology, Bruch Membrane diagnostic imaging, Macular Degeneration diagnosis, Macular Degeneration physiopathology, Tomography, Optical Coherence methods, Retinal Pigment Epithelium pathology, Retinal Pigment Epithelium diagnostic imaging, Aging physiology
- Abstract
Purpose: A micrometer scale hyporeflective band within the retinal pigment epithelium basal lamina - Bruch's membrane complex (RPE-BL-BrM) was topographically measured in aging and age-related macular degeneration (AMD)., Methods: In a prospective cross-sectional study, 90 normal eyes from 76 subjects (range = 23-90 years) and 53 dry AMD eyes from 47 subjects (range = 62-91 years) were enrolled. Isotropic volume raster scans over 6 mm × 6 mm (500 × 500 A-scans) were acquired using a high-resolution (2.7 µm axial resolution) spectral-domain optical coherence tomography (SD-OCT) prototype instrument. Six consecutive optical coherence tomography (OCT) volumes were computationally motion-corrected and fused to improve feature visibility. A boundary regression neural network was developed to measure hyporeflective band thickness. Topographic dependence was evaluated over a 6-mm-diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid., Results: The hyporeflective band thickness map (median of 4.3 µm and 7.8 µm in normal and AMD eyes, respectively) is thicker below and radially symmetric around the fovea. In normal eyes, age-associated differences occur within 0.7 to 2.3 mm from the foveal center (P < 0.05). In AMD eyes, the hyporeflective band is hypothesized to be basal laminar deposits (BLamDs) and is thicker within the 3-mm ETDRS circle (P < 0.0002) compared with normal eyes. The inner ring is the most sensitive location to detect age versus AMD-associated changes within the RPE-BL-BrM. AMD eyes with subretinal drusenoid deposits (SDDs) have a significantly thicker hyporeflective band (P < 0.001) than those without SDDs., Conclusions: The hyporeflective band is a quantifiable biomarker which differentiates AMD from aging. Longitudinal studies are warranted. The hyporeflective band may be a useful biomarker for risk stratification and disease progression. more...
- Published
- 2024
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31. Extent and Topography of Subretinal Drusenoid Deposits Associate With Rod-Mediated Vision in Aging and AMD: ALSTAR2 Baseline.
- Author
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Goerdt L, Amjad M, Swain TA, McGwin G, Clark ME, Owsley C, Sloan KR, Curcio CA, and Kar D
- Subjects
- Humans, Female, Aged, Male, Middle Aged, Aging physiology, Aged, 80 and over, Fluorescein Angiography methods, Deep Learning, Tomography, Optical Coherence methods, Retinal Drusen diagnosis, Retinal Drusen physiopathology, Dark Adaptation physiology, Retinal Rod Photoreceptor Cells physiology, Retinal Rod Photoreceptor Cells pathology, Macular Degeneration physiopathology, Macular Degeneration diagnosis, Visual Acuity physiology
- Abstract
Purpose: In AMD, rod-mediated dark adaptation (RMDA) at 5° eccentricity is slower in eyes with subretinal drusenoid deposits (SDDs) than in eyes without. Here we quantified SDD burden using supervised deep learning for comparison to vision and photoreceptor topography., Methods: In persons ≥60 years from the Alabama Study on Early Age-Related Macular Degeneration 2, normal, early AMD, and intermediate AMD eyes were classified by the AREDS nine-step system. A convolutional neural network was trained on 55°-wide near-infrared reflectance images for SDD segmentation. Trained graders annotated ground truth (SDD yes/no). Predicted and true datasets agreed (Dice coefficient, 0.92). Inference was manually proofread using optical coherence tomography. The mean SDD area (mm2) was compared among diagnostic groups (linear regression) and to vision (age-adjusted Spearman correlations). Fundus autofluorescence images were used to mask large vessels in SDD maps., Results: In 428 eyes of 428 persons (normal, 218; early AMD, 120; intermediate AMD, 90), the mean SDD area differed by AMD severity (P < 0.0001): 0.16 ± 0.87 (normal), 2.48 ± 11.23 (early AMD), 11.97 ± 13.33 (intermediate AMD). Greater SDD area was associated with worse RMDA (r = 0.27; P < 0.0001), mesopic (r = -0.13; P = 0.02) and scotopic sensitivity (r = -0.17; P < 0.001). SDD topography peaked at 5° superior, extended beyond the Early Treatment of Diabetic Retinopathy Study grid and optic nerve, then decreased., Conclusions: SDD area is associated with degraded rod-mediated vision. RMDA 5° (superior retina) probes where SDD is maximal, closer to the foveal center than the rod peak at 3 to 6 mm (10.4°-20.8°) superior and the further eccentric peak of rod:cone ratio. Topographic data imply that factors in addition to rod density influence SDD formation. more...
- Published
- 2024
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32. Repeatability of Rod-Mediated Dark Adaptation Testing in Normal Aging and Early and Intermediate Age-Related Macular Degeneration.
- Author
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Owsley C, Swain TA, McGwin G Jr, Bernard MM, Clark ME, and Curcio CA
- Subjects
- Humans, Aged, Male, Female, Reproducibility of Results, Aged, 80 and over, Middle Aged, Vision Tests, Dark Adaptation physiology, Retinal Rod Photoreceptor Cells physiology, Aging physiology, Visual Acuity physiology, Macular Degeneration physiopathology, Macular Degeneration diagnosis
- Abstract
Purpose: The vulnerability of rod photoreceptors in aging and early and intermediate age-related macular degeneration (AMD) has been well documented. Rod-mediated dark adaptation (RMDA) is a measure of the recovery of light sensitivity in rod photoreceptors following a bright light. Delays in RMDA during early and intermediate AMD have been widely reported. For RMDA's promise as an outcome for trials targeted at early and intermediate AMD to be realized, excellent test-retest reliability, its repeatability, must be established., Methods: Test-retest performance in a commonly used RMDA test based on the rod intercept time metric (RIT) was evaluated in participants with early and intermediate AMD and with normal retinal aging with testing approximately 2 weeks apart. The test target was placed at 5° eccentricity superior to the foveal center, an area with maximal rod loss in aging and AMD. Disease severity was identified by a trained and masked grader of fundus photographs using both the AREDS 9-step and Beckman classification systems. Bland-Altman plots and intra-class correlation coefficients (ICC) evaluated repeatability., Results: The analysis sample consisted of 37 older adults (mean age 76 years, standard deviation 5), with approximately one-third of the sample in each of three groups - normal aging, early AMD, and intermediate AMD. For the total sample, the ICC was 0.98. For individual AMD groups for both AREDS 9-step and Beckman classifications, the ICCs were also very high ranging from 0.82 to 0.99., Conclusion: We demonstrated that RMDA testing using the RIT metric has excellent repeatability when target location is at 5° in studying older adults from normal aging to intermediate AMD, suggesting the reliable use of this functional measure in trials. more...
- Published
- 2024
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33. Choriocapillaris Impairment, Visual Function, and Distance to Fovea in Aging and Age-Related Macular Degeneration: ALSTAR2 Baseline.
- Author
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Kar D, Amjad M, Corradetti G, Swain TA, Clark ME, McGwin G Jr, Sloan KR, Owsley C, Sadda SR, and Curcio CA
- Subjects
- Humans, Male, Aged, Female, Middle Aged, Aged, 80 and over, Choroid blood supply, Choroid diagnostic imaging, Tomography, Optical Coherence methods, Visual Acuity physiology, Fovea Centralis diagnostic imaging, Fovea Centralis pathology, Fovea Centralis blood supply, Fovea Centralis physiopathology, Aging physiology, Macular Degeneration physiopathology, Fluorescein Angiography methods, Dark Adaptation physiology
- Abstract
Purpose: In aging and early-intermediate age-related macular degeneration (AMD), rod-mediated dark adaptation (RMDA) slows more at 5° superior than at 12°. Using optical coherence tomography angiography (OCTA), we asked whether choriocapillaris flow deficits are related to distance from the fovea., Methods: Persons ≥60 years stratified for AMD via the Age-Related Eye Disease Study's nine-step system underwent RMDA testing. Two adjacent 4.4° × 4.4° choriocapillaris OCTA slabs were centered on the fovea and 12° superior. Flow signal deficits (FD%) in concentric arcs (outer radii in mm, 0.5, 1.5, 2.2, 4.0, and 5.0 superior) were correlated with rod intercept time (RIT) and best-corrected visual acuity (BCVA)., Results: In 366 eyes (170 normal, 111 early AMD, 85 intermediate AMD), FD% was significantly worse with greater AMD severity in all regions (overall P < 0.05) and poorest under the fovea (P < 0.0001). In pairwise comparisons, FD% worsened with greater AMD severity (P < 0.05) at distances <2.2 mm. At greater distances, eyes with intermediate, but not early AMD differed from normal eyes. Foveal FD% was more strongly associated with longer RIT at 5° (r = 0.52) than RIT at 12° (r = 0.39) and BCVA (r = 0.21; all P < 0.0001). Choroidal thickness was weakly associated with longer RIT at 5° and 12° (r = 0.10-0.20, P < 0.05) and not associated with AMD severity., Conclusions: Reduced transport across the choriocapillaris-Bruch's membrane-retinal pigment epithelium complex, which contributes to drusen formation under the macula lutea (and fovea), may also reduce retinoid resupply to rods encircling the high-risk area. FD% has potential as a functionally validated imaging biomarker for AMD emergence. more...
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- 2024
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34. Unusual morphology of foveal Müller glia in an adult human born pre-term.
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Kar D, Singireddy R, Kim YJ, Packer O, Schalek R, Cao D, Sloan KR, Pollreisz A, Dacey DM, and Curcio CA
- Abstract
The fovea of the human retina, a specialization for acute and color vision, features a high concentration of cone photoreceptors. A pit on the inner retinal aspect is created by the centrifugal migration of post-receptoral neurons. Foveal cells are specified early in fetal life, but the fovea reaches its final configuration postnatally. Pre-term birth retards migration resulting in a small pit, a small avascular zone, and nearly continuous inner retinal layers. To explore the involvement of Müller glia, we used serial-section electron microscopic reconstructions to examine the morphology and neural contacts of Müller glia contacting a single foveal cone in a 28-year-old male organ donor born at 28 weeks of gestation. A small non-descript foveal avascular zone contained massed glial processes that included a novel class of 'inner' Müller glia. Similar to classic 'outer' Müller glia that span the retina, inner Müller glia have bodies in the inner nuclear layer (INL). These cells are densely packed with intermediate filaments and insert processes between neurons. Unlike 'outer' Müller glia, 'inner' Müller glia do not reach the external limiting membrane but instead terminate at the outer plexiform layer. One completely reconstructed inner cell ensheathed cone pedicles and a cone-driven circuit of midget bipolar and ganglion cells. Inner Müller glia outnumber foveal cones by 1.8-fold in the outer nuclear layer (221,448 vs. 123,026 cells/mm
2 ). Cell bodies of inner Müller glia outnumber those of outer Müller glia by 1.7-fold in the INL (41,872 vs. 24,631 cells/ mm2 ). Müller glia account for 95 and 80% of the volume of the foveal floor and Henle fiber layer, respectively. Determining whether inner cells are anomalies solely resulting from retarded lateral migration of inner retinal neurons in pre-term birth requires further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kar, Singireddy, Kim, Packer, Schalek, Cao, Sloan, Pollreisz, Dacey and Curcio.) more...- Published
- 2024
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35. A cell culture system for RPE hypoxia, a physiologic stressor relevant to AMD deposit formation.
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Curcio CA and Goerdt L
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- 2024
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36. Outer Retinal Thickness Is Associated With Cognitive Function in Normal Aging to Intermediate Age-Related Macular Degeneration.
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Owsley C, McGwin G Jr, Swain TA, Clark ME, Thomas TN, Goerdt L, Sloan KR, Trittschuh EH, Jiang Y, Owen JP, Lee CS, and Curcio CA
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- Humans, Male, Aged, Female, Cross-Sectional Studies, Aged, 80 and over, Nerve Fibers pathology, Retinal Ganglion Cells pathology, Tomography, Optical Coherence methods, Aging physiology, Macular Degeneration physiopathology, Cognition physiology, Retina diagnostic imaging, Retina pathology, Retina physiopathology
- Abstract
Purpose: Research on Alzheimer's disease (AD) and precursor states demonstrates a thinner retinal nerve fiber layer (NFL) compared to age-similar controls. Because AD and age-related macular degeneration (AMD) both impact older adults and share risk factors, we asked if retinal layer thicknesses, including NFL, are associated with cognition in AMD., Methods: Adults ≥ 70 years with normal retinal aging, early AMD, or intermediate AMD per Age-Related Eye Disease Study (AREDS) nine-step grading of color fundus photography were enrolled in a cross-sectional study. Optical coherence tomography (OCT) volumes underwent 11-line segmentation and adjustments by a trained operator. Evaluated thicknesses reflect the vertical organization of retinal neurons and two vascular watersheds: NFL, ganglion cell layer-inner plexiform layer complex (GCL-IPL), inner retina, outer retina (including retinal pigment epithelium-Bruch's membrane), and total retina. Thicknesses were area weighted to achieve mean thickness across the 6-mm-diameter Early Treatment of Diabetic Retinopathy Study (ETDRS) grid. Cognitive status was assessed by the National Institutes of Health Toolbox cognitive battery for fluid and crystallized cognition. Correlations estimated associations between cognition and thicknesses, adjusting for age., Results: Based on 63 subjects (21 per group), thinning of the outer retina was significantly correlated with lower cognition scores (P < 0.05). No other retinal thickness variables were associated with cognition., Conclusions: Only the outer retina (photoreceptors, supporting glia, retinal pigment epithelium, Bruch's membrane) is associated with cognition in aging to intermediate AMD; NFL was not associated with cognition, contrary to AD-associated condition reports. Early and intermediate AMD constitute a retinal disease whose earliest, primary impact is in the outer retina. Our findings hint at a unique impact on the brain from the outer retina in persons with AMD. more...
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- 2024
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37. Probing Deposit-Driven Age-Related Macular Degeneration Via Thicknesses of Outer Retinal Bands and Choroid: ALSTAR2 Baseline.
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Emamverdi M, Vatanatham C, Fasih-Ahmad S, Wang Z, Mishra Z, Jain A, Ganegoda A, Clark ME, Habibi A, Ashrafkhorasani M, Owsley C, Curcio CA, Hu ZJ, and Sadda SR
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Cross-Sectional Studies, Retinal Photoreceptor Cell Outer Segment pathology, Visual Acuity physiology, Choroid pathology, Choroid diagnostic imaging, Macular Degeneration diagnosis, Retinal Drusen diagnosis, Retinal Pigment Epithelium pathology, Retinal Pigment Epithelium diagnostic imaging, Tomography, Optical Coherence methods
- Abstract
Purpose: We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography (OCT) in a well-characterized, large cross-sectional cohort., Methods: Subjects ≥ 60 years with healthy normal eyes, as well as early or intermediate AMD were enrolled in the Alabama Study on Age-related Macular Degeneration 2 (ALSTAR2; NCT04112667). Using Spectralis HRA + OCT2, we obtained macular volumes for each participant. An auto-segmentation software was used to segment six layers and sublayers: photoreceptor inner and outer segments, subretinal drusenoid deposits (SDDs), retinal pigment epithelium + basal lamina (RPE + BL), drusen, and choroid. After manually refining the segmentations of all B-scans, mean thicknesses in whole, central, inner and outer rings of the ETDRS grid were calculated and compared among groups., Results: This study involved 502 patients, 252 were healthy, 147 had early AMD, and 103 had intermediate AMD eyes (per Age-Related Eye Disease Study [AREDS] 9-step). Intermediate AMD eyes exhibited thicker SDD and drusen, thinner photoreceptor inner segments, and RPE compared to healthy and early AMD eyes. They also had thicker photoreceptor outer segments than early AMD eyes. Early AMD eyes had thinner photoreceptor outer segments than normal eyes but a thicker choroid than intermediate AMD eyes. Using the Beckman scale, 42% of the eyes initially classified as early AMD shifted to intermediate AMD, making thickness differences for photoreceptor outer segments and choroid insignificant., Conclusions: With AMD stages, the most consistent structural differences involve appearance of drusen and SDD, followed by RPE + BL thickness, and then thickness of photoreceptor inner and outer segments. Structural changes in the transition from aging to intermediate AMD include alterations in the outer retinal bands, including the appearance of deposits on either side of the RPE. more...
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- 2024
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38. Biomarkers in age-related macular degeneration.
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Balaratnasingam C and Curcio CA
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- Humans, Biomarkers blood, Macular Degeneration diagnosis
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- 2024
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39. Quantitative Autofluorescence at AMD's Beginnings Highlights Retinal Topography and Grading System Differences: ALSTAR2 Baseline.
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Berlin A, Fischer NA, Clark ME, Kar D, Swain TA, Martindale RM, McGwin G Jr, Crosson JN, Sloan KR, Owsley C, and Curcio CA
- Abstract
Introduction: The aims of the study were to describe baseline quantitative (short-wavelength) autofluorescence (qAF) findings in a large pseudophakic cohort at age-related macular degeneration (AMD)'s beginnings and to assess qAF8 as an outcome measure and evaluate Age-Related Eye Disease Study (AREDS) and Beckman grading systems., Methods: In the ALSTAR2 baseline cohort (NCT04112667), 346 pseudophakic eyes of 188 persons (74.0 ± 5.5 years) were classified as normal (N = 160 by AREDS, 158 by Beckman), early AMD (eAMD) (N = 104, 66), and intermediate AMD (iAMD) (N = 82, 122). Groups were compared via mean qAF intensities in a 6°-8° annulus (qAF8) and maps of differences between observations and the overall mean, divided by standard deviation (Z-score)., Results: qAF8 did not differ significantly among diagnostic groups by either stratification (p = 0.0869 AREDS; p = 0.0569 by Beckman). Notably, 45 eyes considered eAMD by AREDS became iAMD by Beckman. For AREDS-stratified eyes, Z-score maps showed higher centrally located qAF for normal, near the mean in eAMD, and lower values for iAMD. Maps deviated from this pattern for Beckman-stratified eyes., Conclusions: In a large sample of pseudophakic eyes, qAF8 does not differ overall from normal aging to iAMD but also does not capture the earliest AMD activity in the macula lutea. AREDS classification gives results more consistent with a slow decline in histologic autofluorescence than Beckman classification., (© 2024 S. Karger AG, Basel.) more...
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- 2024
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40. Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.
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Grubaugh CR, Dhingra A, Prakash B, Montenegro D, Sparrow JR, Daniele LL, Curcio CA, Bell BA, Hussain MM, and Boesze-Battaglia K
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- Animals, Mice, Retinoids, Apolipoproteins B genetics, Homeostasis, Retina, Retinal Pigment Epithelium, Carrier Proteins
- Abstract
Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor-associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE-specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.) more...
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- 2024
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41. Age-Related Macular Degeneration, a Mathematically Tractable Disease.
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Curcio CA, Kar D, Owsley C, Sloan KR, and Ach T
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- Humans, Adult, Aged, Retina, Retinal Cone Photoreceptor Cells, Macular Degeneration, Macula Lutea, Geographic Atrophy
- Abstract
A progression sequence for age-related macular degeneration onset may be determinable with consensus neuroanatomical nomenclature augmented by drusen biology and eye-tracked clinical imaging. This narrative review proposes to supplement the Early Treatment of Diabetic Retinopathy Study (sETDRS) grid with a ring to capture high rod densities. Published photoreceptor and retinal pigment epithelium (RPE) densities in flat mounted aged-normal donor eyes were recomputed for sETDRS rings including near-periphery rich in rods and cumulatively for circular fovea-centered regions. Literature was reviewed for tissue-level studies of aging outer retina, population-level epidemiology studies regionally assessing risk, vision studies regionally assessing rod-mediated dark adaptation (RMDA), and impact of atrophy on photopic visual acuity. The 3 mm-diameter xanthophyll-rich macula lutea is rod-dominant and loses rods in aging whereas cone and RPE numbers are relatively stable. Across layers, the largest aging effects are accumulation of lipids prominent in drusen, loss of choriocapillary coverage of Bruch's membrane, and loss of rods. Epidemiology shows maximal risk for drusen-related progression in the central subfield with only one third of this risk level in the inner ring. RMDA studies report greatest slowing at the perimeter of this high-risk area. Vision declines precipitously when the cone-rich central subfield is invaded by geographic atrophy. Lifelong sustenance of foveal cone vision within the macula lutea leads to vulnerability in late adulthood that especially impacts rods at its perimeter. Adherence to an sETDRS grid and outer retinal cell populations within it will help dissect mechanisms, prioritize research, and assist in selecting patients for emerging treatments. more...
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- 2024
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42. Shotgun lipidomics of human subretinal fluids under rod-dominant retina reveals cone-dominated lipids.
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Chen J, Curcio CA, and Crosson JN
- Subjects
- Humans, Subretinal Fluid metabolism, Cholesterol Esters metabolism, Lipidomics, Retina metabolism, Retinal Detachment metabolism
- Abstract
Subretinal fluid (SRF) accumulates between photoreceptor outer segments and retinal pigment epithelium during rhegmatogenous retinal detachment. Biomolecular components such as lipids originate from cells surrounding the SRF. Knowledge of the composition of these molecules in SRF potentially provides mechanistic insight into the physiologic transfer of lipids between retinal tissue compartments. Using mass spectrometry and tandem mass spectrometry analysis on an electrospray ionization quadrupole-time-of-flight mass spectrometer, we identified a total of 115 lipid molecular species of 11 subclasses and 9 classes in two samples from two patients with rhegmatogenous retinal detachment. These included 47 glycerophosphocholines, 6 glycerophosphoethanolamines, 1 glycerophosphoinositol, 18 sphingomyelins, 9 cholesteryl esters, free cholesterol, 3 ceramides, 22 triacylglycerols and 8 free fatty acids. Glycerophosphocholines were of the highest intensity. By minimizing the formation of different adduct forms or clustering ions of different adducts, we determined the relative intensity of lipid molecular species within the same subclasses. The profiles were compared with those of retinal cells available in the published literature. The glycerophosphocholine profile of SRF was similar to that of cone outer segments, suggesting that outer segment degradation products are constitutively released into the interphotoreceptor matrix, appearing in SRF during detachment. This hypothesis was supported by the retinal distributions of corresponding lipid synthases' mRNA expression obtained from an online resource based on publicly available single-cell sequencing data. In contrast, based on lipid profiles and relevant gene expression in this study, the sources of free cholesterol and cholesteryl esters in SRF appeared more ambiguous, possibly reflecting that outer retina takes up plasma lipoproteins. Further studies to identify and quantify lipids in SRF will help better understand etiology of diseases relevant to outer retina., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...
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- 2024
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43. Potential Structural Biomarkers in 3D Images Validated by the First Functional Biomarker for Early Age-Related Macular Degeneration - ALSTAR2 Baseline.
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Fasih-Ahmad S, Wang Z, Mishra Z, Vatanatham C, Clark ME, Swain TA, Curcio CA, Owsley C, Sadda SR, and Hu ZJ
- Subjects
- Humans, Retina, Fovea Centralis, Biomarkers, Nonoxynol, Macular Degeneration diagnosis, Macula Lutea
- Abstract
Purpose: Lack of valid end points impedes developing therapeutic strategies for early age-related macular degeneration (AMD). Delayed rod-mediated dark adaptation (RMDA) is the first functional biomarker for incident early AMD. The relationship between RMDA and the status of outer retinal bands on optical coherence tomography (OCT) have not been well defined. This study aims to characterize these relationships in early and intermediate AMD., Methods: Baseline data from 476 participants was assessed including eyes with early AMD (n = 138), intermediate AMD (n = 101), and normal aging (n = 237). Participants underwent volume OCT imaging of the macula and rod intercept time (RIT) was measured. The ellipsoid zone (EZ) and interdigitation zone (IZ) on all OCT B-scans of the volumes were segmented. The area of detectable EZ and IZ, and mean thickness of IZ within the Early Treatment Diabetic Retinopathy Study (ETDRS) grid were computed and associations with RIT were assessed by Spearman's correlation coefficient and age adjusted., Results: Delayed RMDA (longer RIT) was most strongly associated with less preserved IZ area (r = -0.591; P < 0.001), followed by decreased IZ thickness (r = -0.434; P < 0.001), and EZ area (r = -0.334; P < 0.001). This correlation between RIT and IZ integrity was not apparent when considering normal eyes alone within 1.5 mm of the fovea., Conclusions: RMDA is correlated with the status of outer retinal bands in early and intermediate AMD eyes, particularly, the status of the IZ. This correlation is consistent with a previous analysis of only foveal B-scans and is biologically plausible given that retinoid availability, involving transfer at the interface attributed to the IZ, is rate-limiting for RMDA. more...
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- 2024
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44. Spectral Analysis of Human Retinal Pigment Epithelium Cells in Healthy and AMD Eyes.
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Bourauel L, Vaisband M, von der Emde L, Bermond K, Tarau IS, Heintzmann R, Holz FG, Curcio CA, Hasenauer J, and Ach T
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- Humans, Retinal Pigment Epithelium metabolism, Bruch Membrane metabolism, Macular Degeneration diagnosis, Macular Degeneration metabolism, Geographic Atrophy metabolism, Macula Lutea metabolism
- Abstract
Purpose: Retinal pigment epithelium (RPE) cells show strong autofluorescence (AF). Here, we characterize the AF spectra of individual RPE cells in healthy eyes and those affected by age-related macular degeneration (AMD) and investigate associations between AF spectral response and the number of intracellular AF granules per cell., Methods: RPE-Bruch's membrane flatmounts of 22 human donor eyes, including seven AMD-affected eyes (early AMD, three; geographic atrophy, one; neovascular, three) and 15 unaffected macula (<51 years, eight; >80 years, seven), were imaged at the fovea, perifovea, and near-periphery using confocal AF microscopy (excitation 488 nm), and emission spectra were recorded (500-710 nm). RPE cells were manually segmented with computer assistance and stratified by disease status, and emission spectra were analyzed using cubic spline transforms. Intracellular granules were manually counted and classified. Linear mixed models were used to investigate associations between spectra and the number of intracellular granules., Results: Spectra of 5549 RPE cells were recorded. The spectra of RPE cells in healthy eyes showed similar emission curves that peaked at 580 nm for fovea and perifovea and at 575 and 580 nm for near-periphery. RPE spectral curves in AMD eyes differed significantly, being blue shifted by 10 nm toward shorter wavelengths. No significant association coefficients were found between wavelengths and granule counts., Conclusions: This large series of RPE cell emission spectra at precisely predefined retinal locations showed a hypsochromic spectral shift in AMD. Combining different microscopy techniques, our work has identified cellular RPE spectral AF and subcellular granule properties that will inform future in vivo investigations using single-cell imaging. more...
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- 2024
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45. Assessment of The Utility of The Sarcoma DNA Methylation Classifier In Surgical Pathology.
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Miettinen M, Abdullaev Z, Turakulov R, Quezado M, Luiña Contreras A, Curcio CA, Rys J, Chlopek M, Lasota J, and Aldape KD
- Subjects
- Humans, DNA Methylation, Transferases genetics, DNA, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Melanoma genetics, Pathology, Surgical, Sarcoma diagnosis, Sarcoma genetics, Liposarcoma genetics, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms genetics, Neurilemmoma genetics, Neurofibrosarcoma genetics
- Abstract
Diagnostic classification of soft tissue tumors is based on histology, immunohistochemistry, genetic findings, and radiologic and clinical correlations. Recently, a sarcoma DNA methylation classifier was developed, covering 62 soft tissue and bone tumor entities. The classifier is based on large-scale analysis of methylation sites across the genome. It includes DNA copy number analysis and determines O 6 methylguanine DNA methyl-transferase methylation status. In this study, we evaluated 619 well-studied soft tissue and bone tumors with the sarcoma classifier. Problem cases and typical examples of different entities were included. The classifier had high sensitivity and specificity for fusion sarcomas: Ewing, synovial, CIC -rearranged, and BCOR -rearranged. It also performed well for leiomyosarcoma, malignant peripheral nerve sheath tumors (MPNST), and malignant vascular tumors. There was low sensitivity for diagnoses of desmoid fibromatosis, neurofibroma, and schwannoma. Low specificity of matches was observed for angiomatoid fibrous histiocytoma, inflammatory myofibroblastic tumor, Langerhans histiocytosis, schwannoma, undifferentiated sarcoma, and well-differentiated/dedifferentiated liposarcoma. Diagnosis of lipomatous tumors was greatly assisted by the detection of MDM2 amplification and RB1 loss in the copy plot. The classifier helped to establish diagnoses for KIT-negative gastrointestinal stromal tumors, MPNSTs with unusual immunophenotypes, and undifferentiated melanomas. O 6 methylguanine DNA methyl-transferase methylation was infrequent and most common in melanomas (35%), MPNSTs (11%), and undifferentiated sarcomas (11%). The Sarcoma Methylation Classifier will likely evolve with the addition of new entities and refinement of the present methylation classes. The classifier may also help to define new entities and give new insight into the interrelationships of sarcomas., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.) more...
- Published
- 2024
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46. Rod mediated dark adaptation, a functional test for early and intermediate AMD outcomes.
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Owsley C, Swain TA, Kar D, and Curcio CA
- Abstract
Competing Interests: Declaration of interest The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. more...
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- 2024
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47. Deep Learning Assisted Imaging Methods to Facilitate Access to Ophthalmic Telepathology.
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Browne AW, Kim G, Vu AN, To JK, Minckler DS, Estopinal MDV, Rao NA, Curcio CA, and Baldi PF
- Abstract
Purpose: To investigate the use of super-resolution imaging techniques to enable telepathology using low-cost commercial cameras., Design: Experimental study., Participants: A total of 139 ophthalmic pathology slides obtained from the Ophthalmic Pathology service at the University of California, Irvine., Methods: Denoising Diffusion Probabilistic Model (DDPM) was developed to predict super-resolution pathology slide images from low-resolution inputs. The model was pretrained using 150 000 images randomly sampled from the ImageNet dataset. Patch aggregation was used to generate large images with DDPM. The performance of DDPM was evaluated against that of generative adversarial networks (GANs) and Robust UNet, which were also trained on the same dataset., Main Outcome Measures: The performance of models trained to generate super-resolution output images from low-resolution input images can be evaluated by using the mean squared error (MSE) and Structural Similarity Index Measure (SSIM), as well as subjective grades provided by expert pathologist graders., Results: In total, our study included 110 training images, 9 validation images, and 20 testing images. The objective performance scores were averaged over patches generated from 20 test images. The DDPM-based approach with pretraining produced the best results, with an MSE score of 1.35e-5 and an SSIM score of 0.8987. A qualitative analysis of super-resolution images was conducted by expert 3 pathologists and 1 expert ophthalmic microscopist, and the average accuracy of identifying the correct ground truth images ranged from 25% to 70% (with an average accuracy of 46.5%) for widefield images and 25% to 60% (with an average accuracy of 38.25%) for individual patches., Conclusions: The DDPM-based approach with pretraining is assessed to be effective at super-resolution prediction for ophthalmic pathology slides both in terms of objective and subjective measures. The proposed methodology is expected to decrease the reliance on costly slide scanners for acquiring high-quality pathology slide images, while also streamlining clinical workflow and expanding the scope of ophthalmic telepathology., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.) more...
- Published
- 2023
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48. Imaging Modalities for Assessing the Vascular Component of Diabetic Retinal Disease: Review and Consensus for an Updated Staging System.
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Tan TE, Jampol LM, Ferris FL, Tadayoni R, Sadda SR, Chong V, Domalpally A, Blodi BL, Duh EJ, Curcio CA, Antonetti DA, Dutta S, Levine SR, Sun JK, Gardner TW, and Wong TY
- Abstract
Purpose: To review the evidence for imaging modalities in assessing the vascular component of diabetic retinal disease (DRD), to inform updates to the DRD staging system., Design: Standardized narrative review of the literature by an international expert workgroup, as part of the DRD Staging System Update Effort, a project of the Mary Tyler Moore Vision Initiative. Overall, there were 6 workgroups: Vascular Retina, Neural Retina, Systemic Health, Basic and Cellular Mechanisms, Visual Function, and Quality of Life., Participants: The Vascular Retina workgroup, including 16 participants from 4 countries., Methods: Literature review was conducted using standardized evidence grids for 5 modalities: standard color fundus photography (CFP), widefield color photography (WFCP), standard fluorescein angiography (FA), widefield FA (WFFA), and OCT angiography (OCTA). Summary levels of evidence were determined on a validated scale from I (highest) to V (lowest). Five virtual workshops were held for discussion and consensus., Main Outcome Measures: Level of evidence for each modality., Results: Levels of evidence for standard CFP, WFCP, standard FA, WFFA, and OCTA were I, II, I, I, and II respectively. Traditional vascular lesions on standard CFP should continue to be included in an updated staging system, but more studies are required before they can be used in posttreatment eyes. Widefield color photographs can be used for severity grading within the area covered by standard CFPs, although these gradings may not be directly interchangeable with each other. Evaluation of the peripheral retina on WFCP can be considered, but the method of grading needs to be clarified and validated. Standard FA and WFFA provide independent prognostic value, but the need for dye administration should be considered. OCT angiography has significant potential for inclusion in the DRD staging system, but various barriers need to be addressed first., Conclusions: This study provides evidence-based recommendations on the utility of various imaging modalities for assessment of the vascular component of DRD, which can inform future updates to the DRD staging system. Although new imaging modalities offer a wealth of information, there are still major gaps and unmet research needs that need to be addressed before this potential can be realized., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.) more...
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- 2023
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49. Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.
- Author
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Grubaugh CR, Dhingra A, Prakash B, Montenegro D, Sparrow JR, Daniele LL, Curcio CA, Bell BA, Hussain MM, and Boesze-Battaglia K
- Abstract
Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or to age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (apoB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic deletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor -associated cholesterol deposits and photoreceptor cell death, and loss of rod but not cone function. RPE-specific ablation of Mttp had no significant effect on plasma lipids and lipoproteins. While, apoB was decreased in the RPE, ocular retinoid concentrations remained unchanged. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but not directly involved in ocular retinoid and plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function., Competing Interests: Conflict of interest statements: The authors have no conflicts of interest more...
- Published
- 2023
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50. Volumetric Reconstruction of a Human Retinal Pigment Epithelial Cell Reveals Specialized Membranes and Polarized Distribution of Organelles.
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Lindell M, Kar D, Sedova A, Kim YJ, Packer OS, Schmidt-Erfurth U, Sloan KR, Marsh M, Dacey DM, Curcio CA, and Pollreisz A
- Subjects
- Humans, Young Adult, Epithelial Cells, Organelles, Retinal Pigments metabolism, Male, Retina, Retinal Pigment Epithelium metabolism
- Abstract
Purpose: Despite the centrality of the retinal pigment epithelium (RPE) in vision and retinopathy our picture of RPE morphology is incomplete. With a volumetric reconstruction of human RPE ultrastructure, we aim to characterize major membranous features including apical processes and their interactions with photoreceptor outer segments, basolateral infoldings, and the distribution of intracellular organelles., Methods: A parafoveal retinal sample was acquired from a 21-year-old male organ donor. With serial block-face scanning electron microscopy, a tissue volume from the inner-outer segment junction to basal RPE was captured. Surface membranes and complete internal ultrastructure of an individual RPE cell were achieved with a combination of manual and automated segmentation methods., Results: In one RPE cell, apical processes constitute 69% of the total cell surface area, through a dense network of over 3000 terminal branches. Single processes contact several photoreceptors. Basolateral infoldings facing the choriocapillaris resemble elongated filopodia and comprise 22% of the cell surface area. Membranous tubules and sacs of endoplasmic reticulum represent 20% of the cell body volume. A dense basal layer of mitochondria extends apically to partly overlap electron-dense pigment granules. Pores in the nuclear envelope form a distinct pattern of rows aligned with chromatin., Conclusions: Specialized membranes at the apical and basal side of the RPE cell body involved in intercellular uptake and transport represent over 90% of the total surface area. Together with the polarized distribution of organelles within the cell body, these findings are relevant for retinal clinical imaging, therapeutic approaches, and disease pathomechanisms. more...
- Published
- 2023
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