Papers - IKEDA Yasuhiro
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Ishizu M, Murakami Y, Fujiwara K, Funatsu J, Shimokawa S, Nakatake S, Tachibana T, Hisatomi T, Koyanagi Y, Akiyama M, Momozawa Y, Ishibashi T, Sonoda KH, Ikeda Y.
Invest Ophthalmol Vis Sci. 60 ( 13 ) 4462 - 4468 2019.9
Language：English Publishing type：Research paper (scientific journal)
Copyright 2019 The Authors PURPOSE. To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). METHODS. Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) were examined in the RP patients. RESULTS. Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 6 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 6 16.6 U/mL, P ¼ 0.0459). SOD3 was significantly related to visual acuity (r ¼ -0.3701, P ¼ 0.0069) and the average retinal sensitivity of four central points (r ¼ 0.3463, P ¼ 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P ¼ 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/ oxidant markers and visual parameters. CONCLUSIONS. Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP.
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Kaizu Y., Nakao S., Arima M., Wada I., Yamaguchi M., Sekiryu H., Hayami T., Ishikawa K., Ikeda Y., Sonoda K.
Acta Ophthalmologica 97 ( 5 ) e811 - e812 2019.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Acta Ophthalmologica
DOI： 10.1111/aos.14041
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Capillary Dropout is Dominant in Deep Capillary Plexus in Early Diabetic Retinopathy in Optical Coherence Tomography Angiography Reviewed
Kaizu Y, Nakao S, Arima M, Wada I, Yamaguchi M, Sekiryu H, Hayami T, Ishikawa K, Ikeda Y, Sonoda KH
Acta Ophthalmol 2019.8
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1111/aos.14041
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Capillary Dropout is Dominant in Deep Capillary Plexus in Early Diabetic Retinopathy in Optical Coherence Tomography Angiography. Reviewed
Kaizu Y, Nakao S, Arima M, Wada I, Yamaguchi M, Sekiryu H, Hayami T, Ishikawa K, Ikeda Y, Sonoda KH
Acta Ophthalmol 2019.8
Language：English Publishing type：Research paper (other academic)
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Nakatake S., Murakami Y., Funatsu J., Koyanagi Y., Akiyama M., Momozawa Y., Ishibashi T., Sonoda K., Ikeda Y.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 257 ( 6 ) 1169 - 1181 2019.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
PURPOSE: The purpose of the study was to investigate the characteristics of the parafoveal cone density changes in patients with retinitis pigmentosa (RP) using adaptive optics scanning laser ophthalmoscopy (AO-SLO). METHODS: A total of 14 eyes of RP patients and 10 eyes of control subjects were examined. High-resolution images of cone photoreceptor cells were obtained with a Canon AO-SLO system in the four retinal regions of the superior, inferior, temporal, and nasal areas located 1.0 mm from the central fovea. The relationships of cone density with optical coherence tomography (OCT) findings and the visual sensitivity of the static perimetry tests were analyzed in RP patients. RESULTS: The averaged cone densities in RP patients were decreased at 1.0 mm eccentricity from the fovea (11,899 cells/mm2) compared with those in control subjects (16,647 cells/mm2; P < 0.01). The cone density was substantially decreased even in RP patients with an intact interdigitation zone at the examined area (12,865 cells/mm2; P < 0.01 vs. controls) and preserved visual sensitivity with > 35 dB (13,019 cells/mm2; P < 0.001 vs. controls). CONCLUSIONS: In RP, cone photoreceptor cell loss occurred in the parafoveal region with a preserved EZ/IZ or visual sensitivity. AO-SLO may be a useful modality to detect early changes of cone photoreceptor cells in RP patients.
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Night-vision aid using see-through display for patients with retinitis pigmentosa Reviewed
Ikeda Y., Nakatake S., Funatsu J., Fujiwara K., Tachibana T., Murakami Y., Hisatomi T., Yoshida S., Enaida H., Ishibashi T., Sonoda K.
Japanese Journal of Ophthalmology 63 ( 2 ) 181 - 185 2019.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology
© 2019, Japanese Ophthalmological Society. Purpose: From an early stage, retinitis pigmentosa (RP) patients suffer from night blindness which causes nocturnal mobility difficulties. We created a wearable visual aid that uses a high-performance see-through display, and added a high-sensitivity camera with a complementary metal-oxide-semiconductor sensor. Here, we evaluate the device’s efficacy for helping night-blindness sufferers walk in the dark. Study design: Prospective clinical study. Methods: Twenty-eight subjects underwent binocular visual acuity testing in the dark without (power off) and with (power on) the device. The test was carried out in a darkened room. We recorded the number of trial errors and the time it took each subject to arrive at the goal both with and without the aid of our device. Results: Our device effectively assists walking in RP patients with mobility problems in the dark. Conclusion: Binocular visual acuity in the dark was significantly improved with the aid of our device. In the walking test, the number of errors decreased greatly with the device, and the travel time was significantly shortened.
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Ishikawa S., Yoshinaga Y., Kantake D., Nakamura D., Yoshida N., Hisatomi T., Ikeda Y., Ishibashi T., Enaida H.
Graefe's Archive for Clinical and Experimental Ophthalmology 257 ( 3 ) 557 - 565 2019.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: This study was conducted in order to develop a novel noninvasive system for measurement and imaging of the arterial oxygen density ratio (ODR) in the retinal microcirculation. Methods: We developed a system composed of two digital cameras with two different filters, which were attached to a fundus camera capable of simultaneously obtaining two images. Actual measurements were performed on healthy volunteer eyes (n = 61). A new algorithm for ODR measurement and pixel-level imaging of erythrocytes was constructed from these data. The algorithm was based on the morphological closing operation and the line convergence index filter. For system calibration, we compared and verified the ODR values in arterioles and venules that were specified in advance for 56 eyes with reproducibility. In 10 additional volunteers, ODR measurements and imaging of the arterial phase in the retinal microcirculation corresponding to changes in oxygen saturation of the peripheral arteries at normal breathing and breath holding were performed. Results: Estimation of incident light to erythrocytes and pixel-level ODR calculation were achieved using the algorithm. The mean ODR values of arterioles and venules were 0.77 ± 0.060 and 1.02 ± 0.067, respectively. It was possible to separate these regions, calibrate at the pixel level, and estimate the arterial phase. In each of the 10 volunteers, changes in the arterial phase ODR corresponding to changes in oxygen saturation of the peripheral arteries were observed before and after breath holding on ODR images. The mean ODR in 10 volunteers was increased by breath holding (p < 0.05). Conclusions: We developed a basic system for arterial phase ODR measurement and imaging of the retinal microcirculation. With further validation and development, this may provide a useful tool for evaluating retinal oxygen metabolism in the retinal microcirculation.
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Verbakel S., Van Huet R., Den Hollander A., Geerlings M., Kersten E., Klevering B., Klaver C., Plomp A., Wesseling N., Bergen A., Nikopoulos K., Rivolta C., Ikeda Y., Sonoda K., Wada Y., Boon C., Nakazawa T., Hoyng C., Nishiguchi K.
Investigative Ophthalmology and Visual Science 60 ( 4 ) 1192 - 1203 2019.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
© 2019 The Authors. PURPOSE. To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. METHODS. In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. RESULTS. Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14–56) in the patients with arMD/arCRD, 26.2 years (range 18–40) in adRP, and 8.8 years (range 5–12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRPand arRP patients were frame shift and/or nonsense variants located far fromthe C -terminus. CONCLUSIONS. Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.
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Nishiguchi K., Ikeda Y., Fujita K., Kunikata H., Akiho M., Hashimoto K., Hosono K., Kurata K., Koyanagi Y., Akiyama M., Suzuki T., Kawasaki R., Wada Y., Hotta Y., Sonoda K., Murakami A., Nakazawa M., Nakazawa T., Abe T.
Ophthalmology 2019
Language：English Publishing type：Research paper (scientific journal) Publisher：Ophthalmology
© 2019 American Academy of Ophthalmology Purpose: To present phenotypic features of 22 patients with S-antigen (SAG) mutations. Design: Retrospective cohort study. Participants: Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. Methods: Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. Main Outcome Measures: Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. Results: Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. Conclusions: Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP.
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Effect of Ocular Hypertension on D- β -Aspartic Acid-Containing Proteins in the Retinas of Rats Reviewed
Kanamoto T., Tachibana T., Kitaoka Y., Hisatomi T., Ikeda Y., Murakami Y., Tobiume K., Asaoka R., Kiuchi Y.
Journal of Ophthalmology 2019 2019
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Ophthalmology
© 2019 Takashi Kanamoto et al. Purpose. To investigate the effect of ocular hypertension-induced isomerization of aspartic acid in retinal proteins. Methods. Adult Wistar rats with ocular hypertension were used as an experimental model. D-β-aspartic acid-containing proteins were isolated by SDS-PAGE and western blot with an anti-D-β-aspartic acid antibody and identified by liquid chromatography-mass spectrometry analysis. The concentration of ATP was measured by ELISA. Results. D-β-aspartic acid was expressed in a protein band at around 44.5 kDa at much higher quantities in the retinas of rats with ocular hypertension than in those of normotensive rats. The 44.5 kDa protein band was mainly composed of α-enolase, S-arrestin, and ATP synthase subunits α and β, in both the ocular hypertensive and normotensive retinas. Moreover, increasing intraocular pressure was correlated with increasing ATP concentrations in the retinas of rats. Conclusion. Ocular hypertension affected the expression of proteins containing D-β-aspartic acid, including ATP synthase subunits, and up-regulation of ATP in the retinas of rats.
DOI： 10.1155/2019/2431481
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Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients Reviewed
Koyanagi Y., Akiyama M., Nishiguchi K., Momozawa Y., Kamatani Y., Takata S., Inai C., Iwasaki Y., Kumano M., Murakami Y., Omodaka K., Abe T., Komori S., Gao D., Hirakata T., Kurata K., Hosono K., Ueno S., Hotta Y., Murakami A., Terasaki H., Wada Y., Nakazawa T., Ishibashi T., Ikeda Y., Kubo M., Sonoda K.
Journal of Medical Genetics 1 - 9 2019
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Medical Genetics
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Background: The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population. Methods: A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases. Results: We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935∗)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658∗) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases. Conclusions: East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.
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Notomi S., Ishihara K., Efstathiou N.E., Lee J.J., Hisatomi T., Tachibana T., Konstantinou E.K., Ueta T., Murakami Y., Maidana D.E., Ikeda Y., Kume S., Terasaki H., Sonoda S., Blanz J., Young L., Sakamoto T., Sonoda K.H., Saftig P., Ishibashi T., Miller J.W., Kroemer G., Vavvas D.G.
Proceedings of the National Academy of Sciences of the United States of America 116 ( 47 ) 23724 - 23734 2019
Language：English Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences of the United States of America
© 2019 National Academy of Sciences. All rights reserved. The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/ phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch’s membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD—namely, the accumulation of APOE, APOA1, clusterin, and vitronectin—adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch’s membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
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Kaizu Y., Nakao S., Sekiryu H., Wada I., Yamaguchi M., Hisatomi T., Ikeda Y., Kishimoto J., Sonoda K.
Graefe's Archive for Clinical and Experimental Ophthalmology 256 ( 12 ) 2275 - 2282 2018.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Fluorescein angiography (FA) has been conventionally used for detection of retinal nonperfused area (NPA) in diabetic retinopathy (DR) in spite of its qualitative evaluation. Optical coherence tomography angiography (OCTA) has been recently reported to be useful for the quantification of retinal vascular disorder in DR. In this study, we examined whether retinal flow density (FD) measurement in OCTA was useful for NPA detection in DR. Methods: The study included 41 eyes from 29 patients with DR who underwent FA and OCTA. Regions surrounded by arteries or veins were extracted in the OCTA image, and the FDs in each region were measured by Image J. Furthermore, each region was classified as NPA or perfused area (PA) in FA. The receiver operating characteristic (ROC) curve was prepared by logistic regression analysis of the FD. The AUC (area under the ROC curve) and cutoff value of FD were also calculated. Results: Two hundred fifty-two regions were analyzed and classified into 38 NPA regions and 214 PA regions using FA. FD of each capillary plexus in NPA was significantly smaller than in PA (p < 0.0001). The AUC of total capillary plexus layers (TCP), superficial capillary plexus layer (SCP), and deep capillary plexus layer (DCP) was 0.975, 0.974, and 0.971, respectively. All areas, where the FD was more than the cutoff value (0.07 in TCP), were diagnosed with PA. Three areas with intraretinal microvascular abnormalities (IRMA) were diagnosed as PA despite being below the cutoff value. Conclusions: FD measurement in OCTA is useful for NPA detection in DR.
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Assessment of central visual function in patients with retinitis pigmentosa Reviewed
Fujiwara K., Ikeda Y., Murakami Y., Tachibana T., Funatsu J., Koyanagi Y., Nakatake S., Yoshida N., Nakao S., Hisatomi T., Yoshida S., Yoshitomi T., Ishibashi T., Sonoda K.
Scientific Reports 8 ( 1 ) 2018.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
© 2018 The Author(s). In order to clarify the disease progression in retinitis pigmentosa (RP) and its related factors, reliable data on the changes in central visual function in RP are needed. In this longitudinal study, we examined 118 patients who were diagnosed with typical RP. Visual acuity (VA), visual field using a Humphrey Field Analyzer with the central 10-2 SITA-Standard program, and optical coherence tomography measurements were obtained. The slopes, which were derived from serial values of mean deviation (MD), macular sensitivity (MS), or foveal sensitivity (FS) obtained for each eye by a linear mixed model, were used for analysis. MS and FS were calculated as the average retinal sensitivity of 12 and 4 central points respectively. There were statistically significant interactions of times with levels of the central subfield thickness (CST) on the slopes of MS and FS. Compared to the eyes without macular complications, the eyes with macular complications had steeper MD, MS and FS slopes, and this interaction was no significant, but marginal trend for the MS or FS slope (P = 0.10, 0.05, respectively). The central retinal sensitivity (i.e., MS and FS) slopes calculated were effective indices of the progression of central visual function in RP.
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Shiga Y., Akiyama M., Nishiguchi K., Sato K., Shimozawa N., Takahashi A., Momozawa Y., Hirata M., Matsuda K., Yamaji T., Iwasaki M., Tsugane S., Oze I., Mikami H., Naito M., Wakai K., Yoshikawa M., Miyake M., Yamashiro K., Kashiwagi K., Iwata T., Mabuchi F., Takamoto M., Ozaki M., Kawase K., Aihara M., Araie M., Yamamoto T., Kiuchi Y., Nakamura M., Ikeda Y., Sonoda K., Ishibashi T., Nitta K., Iwase A., Shirato S., Oka Y., Satoh M., Sasaki M., Fuse N., Suzuki Y., Cheng C., Khor C., Baskaran M., Perera S., Aung T., Vithana E., Cooke Bailey J., Kang J., Pasquale L., Haines J., Wiggs J., Burdon K., Gharahkhani P., Hewitt A., Mackey D., MacGregor S., Craig J., Rand Allingham R., Hauser M., Ashaye A., Budenz D., Akafo S., Williams S., Kamatani Y., Nakazawa T., Kubo M.
Human Molecular Genetics 27 ( 8 ) 1486 - 1496 2018.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Human Molecular Genetics
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 diseaseassociated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P<5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
DOI： 10.1093/hmg/ddy053
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Sainohira M., Yamashita T., Terasaki H., Sonoda S., Miyata K., Murakami Y., Ikeda Y., Morimoto T., Endo T., Fujikado T., Kamo J., Sakamoto T.
PLoS ONE 13 ( 4 ) 2018.4
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE
© 2018 Sainohira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The purpose of this study is to determine the factors related to anxiety and depression in patients with retinitis pigmentosa (RP). The status of anxiety and depression was determined in RP patients with the Hospital Anxiety and Depression Scale (HADS) questionnaire which consisted of subscales for HADS-anxiety (HADS-A) and HADS-depression (HADS-D). The vision-specific quality of life (VSQOL) was assessed with the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ25). The correlations between the HADS-A or HADS-D scores and vision-related clinical parameters such as the best-corrected visual acuity (BCVA), Functional Acuity Score, Functional Field Score, Functional Vision Score, the NEI- VFQ25 subscale score were determined. The socioeconomic status, such as the work status and membership in the RP society, was investigated to determine the factors related to the HADS-A and HADS-D scores. One hundred and twelve RP patients (46 men and 66 women) with mean age of 60.7±15.4 (standard deviation) years were studied. The HADS-A score was not significantly correlated with any visual functions but was significantly correlated with the general health condition (r = -0.34, P<0.001) and the role limitation (r = -0.20, P = 0.03) of the NEI-VFQ25 subscale. The HADS-D score was significantly correlated with all the visual functions (r = -0.38 to 0.29, P<0.001), the NEI-VFQ25 subscale score (r = - 0.58 to -0.33, P<0.001) by Spearman’s correlations. The HADS-A score was significantly higher in the members of the RP society than in non-members (P = 0.013). The mean HADS-D score of employed individuals was significantly lower than that of unemployed ones (P = 0.001) by the Mann-Whitney U test. The results indicate that visual function impairments and vision-related quality of life are associated with a depressive state, and the general health condition is related to anxiety in RP patients. Being employed may be strongly correlated with the degree of depression in RP patients.
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Koyanagi Y., Yoshida S., Kobayashi Y., Kubo Y., Nakama T., Ishikawa K., Nakao S., Hisatomi T., Ikeda Y., Oshima Y., Ishibashi T., Sonoda K.
Ophthalmologica 239 ( 2-3 ) 94 - 102 2018.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Ophthalmologica
© 2017 S. Karger AG, Basel. Objective: To examine the relationship between early response to anti-vascular endothelial growth factor (VEGF) treatment and visual prognosis. Methods: We retrospectively separated 20 patients with persistent diabetic macular edema (DME) into two responder status groups based on the reduction of central macular thickness (CMT) from baseline to month 3: a delayed responder group (DRG) (≤25% CMT reduction, n = 11) and an immediate responder group (IRG) (>25% CMT reduction, n = 14). We also separated the patients into two responder status groups based on the logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA): a visual nonimprovement group (VNIG) (≥0 logMAR BCVA improvement, n = 11) and a vi sual improvement group (VIG) (<0 logMAR BCVA improvement, n = 14). Finally, we assessed the correlations between logMAR BCVA changes from baseline to month 3 (ΔBCVAM3) and those from baseline to month 12 (ΔBCVAM12). Results: At month 12, BCVA was significantly more improved in the VIG than the VNIG (p < 0.005), but was not significantly different between the DRG and the IRG (p = 0.75). The Pearson correlation coefficient showed a significant relationship between ΔBCVAM3 and ΔBCVAM12 (r = 0.60, p < 0.005). Conclusions: BCVA showed significantly greater improvement in the VIG than in the VNIG. ΔBCVAM3 may predict the visual outcome at month 12 in DME patients treated with anti-VEGF drugs.
DOI： 10.1159/000481711
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Hisatomi T., Tachibana T., Notomi S., Koyanagi Y., Murakami Y., Takeda A., Ikeda Y., Yoshida S., Enaida H., Murata T., Sakamoto T., Sonoda K., Ishibashi T.
Retina 38 ( 3 ) 471 - 479 2018.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Retina
Copyright © by Ophthalmin Communication Society, Inc. Purpose: To examine retinal changes after vitrectomy with internal limiting membrane (ILM) peeling, we used 3-dimensional optical coherence tomography (3D-OCT) in rhegmatogenous retinal detachment cases. Methods: The 68 eyes from 67 patients with rhegmatogenous retinal detachment were studied, including 35 detached macula cases (51%) and 33 attached macula cases. Internal limiting membrane peeling was performed with fine forceps after brilliant blue G staining. The 3D-OCT images were obtained with volume-rendering technologies from cross-sectional OCT images. Results: The 3D-OCT detected 45 eyes (66%) with ILM peeling-dependent retinal changes, including dissociated optic nerve fiber layer appearance, dimple sign, temporal macular thinning, ILM peeling area thinning, or forceps-related retinal thinning. The ILM peeled area was detectable in only 9 eyes with 3D-OCT, whereas it was undetectable in other 59 eyes. The dissociated optic nerve fiber layer appearance was detected in 8 of the total cases (12%), and dimple signs were observed in 14 cases (21%). Forceps-related thinning was also noted in eight cases (24%) of attached macula cases and in four cases (11%) of detached macula cases. No postoperative macular pucker was noted in the observational period. Conclusion: The 3D-OCT clearly revealed spatial and time-dependent retinal changes after ILM peeling. The changes occurred in 2 months and remained thereafter.
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C-Reactive protein and progression of vision loss in retinitis pigmentosa Reviewed
Murakami Y., Ikeda Y., Nakatake S., Fujiwara K., Tachibana T., Yoshida N., Notomi S., Hisatomi T., Yoshida S., Ishibashi T., Sonoda K.
Acta Ophthalmologica 96 ( 2 ) e174 - e179 2018.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Acta Ophthalmologica
© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd Purpose: Chronic inflammation is involved in retinitis pigmentosa (RP). We demonstrated previously that intraocular inflammatory levels, as measured by slit-lamp ophthalmoscopy or laser flare photometry, are inversely correlated with central visual function in patients with RP. Here, we investigated the relationship between serum high-sensitivity C-reactive protein (hs-CRP) and visual parameters in RP. Methods: We studied 58 consecutive typical patients with RP <40 years old and 29 age- and gender-matched controls. High-sensitivity C-reactive protein (hs-CRP) was detected by immunoturbidimetry. The relationships between hs-CRP and visual parameters including best-corrected visual acuity (BCVA), mean deviation (MD) of static perimetry tests (Humphrey Field Analyzer, the central 10-2 programme) and VA changes over the prior 5 years and MD changes over the prior 3 years were analysed in the patients with RP. Results: The serum hs-CRP levels of the patients with RP were significantly higher than those of the controls (0.06 ± 0.08 versus 0.03 ± 0.04 mg/dl, p = 0.0119). In the patients with RP, there was no correlation of hs-CRP with cross-sectionally assessed VA or MD, but the baseline hs-CRP was significantly correlated with the MD deterioration (r = −0.4073, p = 0.0314). Conclusion: The average serum hs-CRP was significantly increased in the patients with RP, and higher hs-CRP was associated with faster deterioration of central visual function. These results suggest that the systemic inflammatory profile is altered and may be associated with disease progression in RP.
DOI： 10.1111/aos.13502
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Koyanagi Y., Murakami Y., Funatsu J., Akiyama M., Nakatake S., Fujiwara K., Tachibana T., Nakao S., Hisatomi T., Yoshida S., Ishibashi T., Sonoda K., Ikeda Y.
Acta Ophthalmologica 96 ( 1 ) e59 - e67 2018.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Acta Ophthalmologica
© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd Purpose: To investigate the macular microvasculature changes by optical coherence tomography angiography (OCTA) and analyse the correlation between these changes and central visual function in patients with retinitis pigmentosa (RP). Methods: We measured the area of the foveal avascular zone (FAZ) and the foveal and parafoveal flow density (FFD and PFD, respectively) in the superficial (S) and deep (D) retinal plexus by OCTA (AngioVue) and compared these values between 73 RP patients and 36 healthy controls. We analysed the relationships between these microvasculature measurements and central visual functions such as visual acuity (VA) and the values of static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) in the RP patients. Results: The FFD-S, PFD-S and PFD-D were significantly decreased in the RP patients compared to the controls (all p < 0.05), whereas there was no significant difference in the FAZ-S, FAZ-D or FFD-D (all p > 0.05). A subgroup analysis showed that the RP patients with VA <20/20 had increased FAZ-S compared to the controls and RP patients with VA ≥20/20 (p = 0.01 and p = 0.007, respectively). Spearman rank testing demonstrated that PFD-S and PFD-D were significantly correlated with all of the central visual parameters (all p < 0.01). The FAZ-S and FFD-S were significantly correlated with VA, and FAZ-D and FFD-D showed no significant correlation. Conclusion: Both the superficial and deep layers of the parafoveal microvasculature are attenuated in RP and correlated with reduced central visual function. The foveal microvasculature, especially in the deep layer, was relatively preserved until mild-to-moderately advanced stages.
DOI： 10.1111/aos.13475