Hypothetical pathogenesis of age-related macular degeneration and pachychoroid diseases derived from their genetic characteristics

Yamashiro, Kenji; Hosoda, Yasuhiro; Miyake, Masahiro; Takahashi, Ayako; Ooto, Sotaro; Tsujikawa, Akitaka

doi:10.1007/s10384-020-00773-w

Cited by 14 publications

(7 citation statements)

References 65 publications

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“…The limitations of this study include the relatively small sample size, retrospective design, and inclusion of both drusen-related and pachychoroid-related AMD 37 ; however, both eyes with thin and thick choroids had similar changes in the CV of the CCFA ratio. The reduction in the CCFA ratio could have reflected the decreased signal reflection from the choriocapillaris due to the deposits in and around the RPE, such as drusen 52 and Bruch's membrane thickening, which may develop before AMD development.…”

Section: Discussionmentioning

confidence: 96%

“… 35 Conversely, recent studies have shown that AMD can be classified according to its estimated etiology into drusen-related AMD, which has a relatively thinner choroid 36 and pachychoroid, and thick choroid-related AMD. 37 Central serous chorioretinopathy (CSC), which is considered to have a similar background as pachychoroid-related AMD, 9 , 37 involves reduced flow in the choriocapillaris. 38 Therefore, choriocapillaris disorder may occur during the progression of both AMD types, theoretically.…”

Section: Discussionmentioning

confidence: 99%

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Choriocapillaris Flow Imbalance in Fellow Eyes in Age-Related Macular Degeneration

Harada

Nagai

Mushiga

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to identify early changes in choriocapillaris flow in patients with age-related macular degeneration (AMD) with no history of macular neovascularization (MNV). Methods Clinical records of fellow eyes of patients with unilateral neovascular AMD without fundus findings and control eyes of otherwise healthy individuals, except for mild cataract, diagnosed at St. Luke's International Hospital from April 2020 to March 2021, were retrospectively analyzed. Optical coherence tomography (OCT) angiography images of the choriocapillaris slab were binarized using the Phansalkar local thresholding methods to evaluate the choriocapillaris flow area (CCFA) and its coefficient of variation (CV). Results The data of 24 AMD fellow eyes (17 for men, 71.7 ± 1.9 years old) and 21 control eyes (11 for men, 69.1 ± 2.0 years old) were analyzed. The mean CCFA ratio was lower in the AMD fellow eyes (58.6 ± 1.2%) than in the control eyes (62.4 ± 1.3%, P = 0.032), and the mean CV of CCFA ratio was greater in the AMD fellow eyes (0.174 ± 0.007) than in the control eyes (0.154 ± 0.007, P = 0.032). Eyes with CCFA ratio <60% and CV of CCFA ratio ≥0.154 had a 4.371-fold higher risk of being AMD fellow eyes (95% confidence interval = 1.029–18.56, P = 0.046). Differences in CV of CCFA ratio between AMD fellow eyes and control eyes were particularly clear in eyes with thick choroids (mean CV of CCFA in control versus AMD fellow eyes with central choroidal thickness ≥220 µm: 0.144 ± 0.005 vs. 0.173 ± 0.007, P = 0.009**). Conclusions Neovascular AMD fellow eyes without MNV had reduced, heterogeneous, and imbalanced choriocapillaris flow, which may constitute early changes in neovascular AMD, although further studies are required.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Choriocapillaris Flow Imbalance in Fellow Eyes in Age-Related Macular Degeneration

Harada

Nagai

Mushiga

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…A previous report [11] demonstrated that a subgroup of eyes with CVH experienced nonresponsiveness to intravitreal aflibercept. There are several reports describing the clinical and genetic differences between patients with AMD and PNV [12,13]. Hata et al [14] documented a lower intraocular VEGF-A concentration in eyes with PNV than in eyes with t-AMD.…”

Section: Discussionmentioning

confidence: 99%

Photodynamic therapy combined with anti-vascular endothelial growth factor therapy for pachychoroid neovasculopathy

et al. 2021

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This multicenter retrospective study was conducted to evaluate the 1-year treatment outcome of photodynamic therapy (PDT) combined with anti-vascular endothelial growth factor (VEGF) therapy for pachychoroid neovasculopathy (PNV). A total of 42 eyes of 42 patients with treatment-naïve PNV who were treated with PDT combined with intravitreal injections of an anti-VEGF agent (ranibizumab or aflibercept) for 1 year. All eyes showed exudative and/or hemorrhagic changes that affected the fovea at baseline. After the initial combination therapy, subfoveal choroidal thickness (SCT) and central retinal thickness (CRT) were significantly reduced and were maintained as such for 12 months (P < 0.01 in SCT and CRT). The best-corrected visual acuity (BCVA) (0.19 ± 0.30 at baseline) significantly improved at 3 months (0.15 ± 0.29, P < 0.05) and further improved at 12 months (0.10 ± 0.30, P < 0.01) when compared to that at baseline. After the initial combination therapy, 32 eyes (76.2%) required no additional treatments for 12 months. The mean number of additional PDT and intravitreal injections of anti-VEGF agents was 0.1 ± 0.3 and 0.9 ± 1.9, respectively. Of the 42 eyes included in this study, 22 eyes (52.4%) had polypoidal lesions at baseline. No significant differences in SCT, CRT, or BCVA were observed at any time points between eyes with and without polypoidal lesions. Of 20 eyes without polypoidal lesions, only 1 eye (5.0%) needed additional treatments. PNV, especially without polypoidal lesions, can be treated effectively with PDT combined with anti-VEGF therapy with few sessions.

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“…Most of the target proteins of HtrA1 are in the extracellular matrix (ECM), and the activity of serine protease expressed by HtrA1 is closely related to the TGF‐β signaling pathway and can inhibit the expression of this signaling pathway (Yamashiro et al. 2020 ). The TGF‐β signaling pathway affects the generation of ECM by regulating downstream molecules (Xiong et al.…”

Section: Discussionmentioning

confidence: 99%

“…In order to further verify the degree of brain injury, we then carried out electron microscopic examination of brain tissue (Figure 4). Interestingly, the electron microscopy results showed that the synapses in ing pathway and can inhibit the expression of this signaling pathway (Yamashiro et al 2020). The TGF-β signaling pathway affects the generation of ECM by regulating downstream molecules (Xiong et al 2019).…”

Section: Discussionmentioning

confidence: 99%

HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF‐β/Smad signaling pathway in CARASIL model mice

Wang

Wen

et al. 2022

Brain and Behavior

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Aims Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a life‐threatening, inherited, nonhypertensive arteriole disease of the brain. Therapeutic strategy for CARASIL is limited because its pathogenesis is not clear. We previously reported the first family with CARASIL in China, which involves a high‐temperature requirement serine protease gene mutation (HtrA1L364P). Based on this previous study, we constructed a CARASIL mouse model (Mut‐hHtrA1L364P mouse, hereinafter referred to as Mut). This paper aimed to systematically study the behavior, pathology, and molecular biology of Mut mice and explore the pathogenesis and possible therapeutic strategies of CARASIL. Methods Food maze and water maze experiments were used in the behavioral studies. Pathological studies were carried out by arteriole labeling staining and electron microscopy. The mRNA and protein expression levels of the key factors of TGF‐β/Smad signaling pathway (TGF‐β, Smad2, Smad3, and Smad4) in the brain of the model mice were detected by immunohistochemistry, real‐time quantitative polymerase chain reaction (RT‐PCR), and Western blot assay. Results The food maze and water maze experiment data showed significant differences between the Mut and wild‐type (WT) mice in the first time to find food, the time to contact the escape table for the first time, and the number of times to travel in the escape table quadrant (p < 0.001). The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure. The results of electron microscopy showed that the cell morphologies in the cortex and hippocampus of Mut mice were abnormal; the number of synapses was reduced; the walls of capillaries, venules, and arterioles thickened; lumen stenosis and other abnormal phenomenon occurred; and lipofuscin deposition and autophagosomes were found in the hippocampus. Immunohistochemistry, RT‐PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF‐β, Smad2, and Smad3 in the brain of Mut mice increased to different degrees. Conclusions The most significant innovation of this study is the first study on the pathogenesis of CARASIL disease using model animals. The Mut mice can well simulate the pathogenesis of CARASIL in behavioral and pathological aspects. The TGF‐β/Smad signaling pathway, which is involved in the pathogenesis of CARASIL, is abnormally upregulated in the brain of Mut mice.

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Hypothetical pathogenesis of age-related macular degeneration and pachychoroid diseases derived from their genetic characteristics

Cited by 14 publications

References 65 publications

Choriocapillaris Flow Imbalance in Fellow Eyes in Age-Related Macular Degeneration

Choriocapillaris Flow Imbalance in Fellow Eyes in Age-Related Macular Degeneration

Photodynamic therapy combined with anti-vascular endothelial growth factor therapy for pachychoroid neovasculopathy

HtrA1L364P leads to cognitive dysfunction and vascular destruction through TGF‐β/Smad signaling pathway in CARASIL model mice

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