Research trends and key topics on inflammation in age-related vision loss over 20 years

The Web of Science served as the primary source for identifying publications pertinent to this study. The search was refined to the “topic” scope, encompassing titles, abstracts, keywords, and additional relevant sections of the articles. The search strategy was formulated as follows: (((((TS= (“age related macular degeneration”)) OR TS= (“age related maculopathy”)) OR TS= (“age related maculopathies”)) OR TS= (“age related macular dystrophy”)) OR TS= (“age related macular dystrophies”)) AND TS= (*inflammation). This initial query yielded 5329 results. Constraints were applied to filter the Web of Science Core Collection (WoSCC) dataset by language (English only) and publication period (2003–2023), with the search executed on September 5th, 2023. Subsequently, a preliminary screening was conducted, followed by a meticulous review by 2 researchers, who scrutinized the titles, abstracts, and full texts of the retrieved documents. Any publication not explicitly addressing inflammation in AMD was excluded. Ultimately, 2044 manuscripts were deemed relevant and selected for in-depth analysis. The selection process is depicted in Figure S1, Supplemental Digital Content, https://links.lww.com/MD/R549↗.

VOSviewer version 1.6.18 was one of the primary tools employed. Prior to the analysis, data was standardized to ensure consistency. To minimize bias, author keywords were manually consolidated; for instance, variations such as “age related macular degeneration” and “age-related macular degeneration” were uniformly categorized under “AMD.” Regarding geographic information, Taiwan was included under the designation of China for analytical purposes. VOSviewer adeptly generated maps illustrating co-occurrence, co-citation, and co-authorship within the dataset. Typically, the size of the nodes or words corresponds to their frequency of occurrence, with larger nodes denoting higher frequency. The lines connecting 2 nodes symbolize their collaborative relationship, with thicker lines indicating more extensive collaboration. Additionally, node colors were assigned to reflect the average publication year of the associated documents.

CiteSpace 6.1. R2 serves as is another bibliometric software employed in this study, designed for generating visual maps derived from database-sourced data. It facilitated the creation of various knowledge-driven visual representations, including maps showcasing citation bursts, timeline views, and dual-map overlays. The configuration for these analyses was carefully set, with the parameters being: 1 year per slice for temporal analysis, application of minimal spanning tree and pruning sliced nets for data refinement, and an inclusion criterion of the top N = 40 most cited or occurring items, with all other settings retained at their default values. In the visualization maps detailing the co-occurrence of countries/regions and institutions, the nodes transition in color from blue to red to denote the progression of publication years from 2003 through to 2023, providing a dynamic overview of the research landscape over time.

Additionally, an online platform (https://bibliometric.com/app_v0↗) was utilized for conducting comparative analyses on the annual publication output among the top 10 contributing countries. For the graphical representation of annual publications, GraphPad Prism 8 and Microsoft Office Excel 365 were employed to craft a column chart and perform descriptive analyses, respectively. The impact factor (IF) scores referenced in this study were obtained from the 2022 Journal Citation Reports, ensuring the most current and relevant data was used for evaluation.

This study is a bibliometric analysis based on data extracted from the Web of Science Core Collection database. Informed consent was therefore not applicable to this study.

Employing the defined search criteria, we identified a total of 2044 papers focused on inflammation in AMD. The annual distribution of publications, as depicted in Figure 1, demonstrates a significant upward trajectory in research output from 2003 to 2023, surpassing the 100-publication mark for the first time in 2014. To quantitatively assess this growth pattern, a power function model (y = 4.8985 × ^1.2383, R² = 0.9248) was constructed, with X representing the year and Y the total number of publications per annum, highlighting a robust increase in scholarly interest over the observed period.

A total of 2164 institutions across 78 countries/regions have contributed to publications on inflammation in AMD. Table 1 showcases the 10 leading countries in this research domain. The publication output from 2003 to 2023 reveals the United States as the forefront contributor with 775 publications, followed by China with 344, United Kingdom with 159, Japan with 142, Germany with 141, England with 136, and Australia with 103 (Fig. 2A). Notably, the United States boasts a centrality score of 0.53, significantly surpassing other nations, indicative of its pivotal role in fostering international collaborations in AMD inflammation research. Here, lines connecting 2 countries represent collaborative efforts (Fig. 2B). Figure 2C further elaborates on these connections, focusing on countries/regions with at least 10 publications. Regarding funding, the top 10 agencies, half of which are American with the United States Department of Health and Human Services emerging as the predominant source of research financing (Fig. 2D).

Figure 3A illustrates the co-occurrences of institutions regarding researches on inflammation in AMD, with Table 2 listing the top 10 contributing institutions. The National Eye Institute (NEI) leads in publication volume (n = 72), closely followed by the University of Eastern Finland (n = 52), Kuopio University Hospital (n = 49), and the University of Melbourne (n = 44). Notably, the NEI boasts the highest count, underscoring its central role and collaborative impact in this field. Among these leading entities, 4 are based in the United States. Additionally, Figure 3B offers an insight into the co-authorship dynamics among these institutions, with a color gradient indicating the recency of average publication years − red denotes the most recent outputs.

Figure 4A showcases the 25 most influential authors in the study of inflammation in AMD, highlighting their publication output. The top 10 among these are further explored in Figure 4B and detailed in Table 3, illustrating their annual scholarly contributions. Kaarniranta, stands out as the leading author with an H-index of 27 and an impressive average citation rate of 51.55 per publication, underscoring the breadth and depth of their impact. Despite a lesser volume of work, Klein, R emerges as the most co-cited author, highlighting the profound influence of their contributions on the field (Table 4). Figure 4C maps the collaborative networks among the top 30 authors, with each author processing a minimum of 12 publications, revealing significant academic collaborations particularly among Kaarniranta, Kauppinen, Hatty and Salminen, as well as collaborations between Xu and Chen. This analysis not only highlights the productivity and scholarly impact of these authors but also the intricate web of collaborations that propel the advancement of research on inflammation in AMD.

Figure 5 unveils the co-citation landscape of authors, zooming in on those who have amassed 110 or more co-citations. Topping the chart, Klein emerges with a remarkable 830 co-citations, closely followed by Seddon with 673 and Hageman with 628 co-citations. Details of these and other top 10 co-cited authors, along with their co-citation figures, are meticulously listed in Table 4. This elite group of authors commands profound respect and recognition across the research domain, as reflected in their substantial co-citation tallies. Through the lens of prolific and co-cited authors, this analysis illuminates their scholarly output, pivotal roles, and the network of collaborations that underscore the collective pursuit of knowledge in the field of inflammation in AMD.

The analysis encompassed articles from 529 journals, with 47 journals each publishing at least 10 papers, as illustrated in Figure 6A. Table 5 lists the top 10 journals contributing to the field, led by Investigative Ophthalmology and Visual Science with 90 publications, followed by Plos One with 70 publications, Experimental Eye Research with 68 publications, International Journal of Molecular Sciences with 66 publications, and Retina-The Journal of Retinal and Vitreous Diseases with 51 publications. Significantly, all journals in the top 10 have an IF above 2 for the year 2022, with 4 achieving Q1 category according to the journal citation reports division. Besides, Table 6 presents the top 10 co-cited journals within this field. Investigative Ophthalmology and Visual Science emerged as the most frequently cited journal, accumulating 10,690 citations, followed by Ophthalmology with 5063 citations, and Proceedings of the National Academy of Sciences of the United States of America with 3596 citations. Notably, the average IF for these top 10 journals is 7.2. Among them, 3 journals boast IFs >10, and 7 are classified within the Q1 category, indicating a strong preference for citing from journals recognized for their high quality. To visualize the interconnectedness of these journals, a dual-map overlay was created using CiteSpace, shown in Figure 6B. This overlay revealed 2 primary citation trajectories, indicating that works published in journals categorized under Molecular/Biology/Immunology or Neurology/Sports/Ophthalmology are predominantly cited by articles in Molecular/Biology/Genetics.

In the Table S1, Supplemental Digital Content, https://links.lww.com/MD/R549↗, we have compiled a list detailing the top 10 most cited papers. Notably, the 10 highest cited articles among these have each achieved over 480 citations. Furthermore, Table 7 outlines the top 10 references with the highest co-citation frequency, with 3 of these studies garnering more than 300 co-citations each. Additionally, we performed an analysis of citation bursts with CiteSpace to pinpoint papers experiencing significant spikes in citations over the past 20 years (Fig. 7). Remarkably, the article authored by Kauppinen in 2016 stands out as the most cited and also ranks highly in terms of co-citation within the AMD inflammation research domain, boasting the most substantial citation burst (strength = 49.6) and drawing considerable focus from the academic community between 2017 and 2021.

The co-occurrence network map visualizes the subject categories appearing at least 50 times, as shown in Figure 8A. Ophthalmology is the most frequent category with 737 occurrences, followed by Biochemistry and Molecular Biology (344 occurrences), Cell Biology (227), and Medicine, Research and Experimental (200). These categories are prominent in AMD research, reflecting their significant contributions to the field. Notably, Biochemistry and Molecular Biology exhibits the highest betweenness centrality at 0.43, underscoring its pivotal role in bridging interdisciplinary research, followed by Pharmacology and Pharmacy (0.31), Medicine, Research and Experimental (0.29), and Immunology (0.23; Table 8). Furthermore, a citation burst analysis was conducted to identify subject categories that have shown notable increases in citations over the past 2 decades. The top 9 categories with the most intense bursts were determined by setting the burst duration to 1 year, as detailed in Figure 8B. Ophthalmology exhibited the most significant citation burst with a strength of 23.83, capturing substantial academic interest from 2003 to 2011. Other categories such as Chemistry, Medicinal, Food Science & Technology, and Chemistry, Multidisciplinary, which continue to be active through 2023, signify the leading-edge disciplines in inflammation research within AMD.

In our study, we utilized author keywords to delve deeply into the prevalent research themes and evolving trends within the domain of inflammation in AMD. Among 3229 identified author keywords, we focused on 53 that appeared no <15 times, leading to the overlay visualization depicted in Figure 9A. This map underscores the intricate connections and relationships among these keywords, showcasing the focal points and areas of keen interest within the inflammation in AMD research domain. Furthermore, Figure 9B lists the top 20 author keywords by frequency, highlighting prominent terms such as “AMD,” “inflammation,” “RPE,” “oxidative stress,” “retina,” “choroidal neovascularization (CNV),” and “complement.” These keywords stand out as the most significant and recurrently mentioned, indicating their central role in current research discussions.

Moreover, Figure 10A presents a thematic evolution analysis, pinpointing the top 15 author keywords based on their prominence within specific timeframes. This analysis employs a 3-field plot to trace the progression of inflammation in AMD research across 3 separate periods. Notably, our findings underscore the heightened focus on “oxidative stress,” “microglia,” and “autophagy” within the last 5 years. These subjects have ascended as central themes, reflecting their escalating significance and pertinence in recent explorations within the realm of AMD research.

Figure 10B showcases a timeline-view graph featuring nodes that represent co-cited references, systematically categorized into 18 distinct thematic clusters through an analysis of author keywords (modularity Q value = 0.7746, weighted mean silhouette value = 0.9147). These clusters include: “age-related macular degeneration” (#0), “complement ‘(#1), ‘oxidative stress’ (#2),’ angiogenesis” (#3), “animal models” (#4), “VEGF” (#5), “neovascularisation” (#6),”leukocyte recruitment” (#7), “ chemoattractant “ (#8), and “autophagy” (#9). Remarkably, “oxidative stress “and “ autophagy “ represent 2 emerging research directions within the field of inflammation in AMD in recent years. These novel areas of investigation signify the evolving research landscape, reflecting the scientific community’s growing interest in the aspect of autophagy and oxidative stress for exploring the pathogenesis of AMD.

Additionally, Figure 11 displays the top 10 author keywords with the most significant citation bursts, highlighting “intraocular inflammation,” “neovascular age-related macular degeneration,” “oxidative stress,” and “diabetic retinopathy” as subjects of significant interest in recent 3 years. These keywords underscore the current research directions, capturing the focal areas of heightened scholarly engagement. The clustering approach used in this analysis, with a modularity Q of 0.68 and a weighted mean silhouette value of 0.89, affirms the method’s logical structure and efficacy in categorizing and pinpointing significant thematic clusters derived from citation trends.

Taken together, this bibliometric analysis demonstrates that research on inflammation in AMD has gradually shifted from descriptive pathological observations toward mechanistic and cellular–molecular investigations. While oxidative stress, complement dysregulation, and innate immune cell activation − particularly involving macrophages and microglia − remain the core mechanistic pillars, recent trends indicate growing interest in autophagy dysfunction, mitochondrial metabolic stress, and lipid-mediated inflammatory signaling. However, current studies largely examine these pathways in isolation, and an integrated perspective explaining how these mechanisms interact to perpetuate chronic retinal inflammation is still lacking. Future research should therefore prioritize cross-omics integration, high-resolution immune microenvironment mapping, and therapeutic strategies aimed at restoring immune-metabolic homeostasis rather than solely suppressing single inflammatory mediators.

The growing research fronts and future research interests in the field of inflammation in AMD over the past nearly 20 years are identified in this study. The data extracted from WoSCC database showed that 9089 authors from 2164 institutions in 78 countries/regions published 2044 papers related to inflammation in AMD in 527 journals between January 1, 2003 and September 5, 2022.

The analysis of publication outputs and trends concerning inflammation in AMD (Fig. 1) revealed a significant increase in scholarly interest and research efforts in this area, particularly noticeable from the year 2014 onwards, where for the first time, annual publications exceeded the 100-paper mark. This pivotal increase can be attributed to a paradigm shift in understanding AMD’s pathophysiology, emphasizing inflammation’s role.^[14] This period also saw significant technological advancements in medical research, increased focus on AMD due to its rising prevalence in an aging population, and enhanced interdisciplinary collaboration.^[1] These factors collectively spurred a marked increase in research activities, as reflected in the exponential growth in the number of publications, aligning with the observed trend in the power function model.

The geographic and institutional contributions to inflammation in AMD research, as illustrated in our analyses, prominently feature the United States and China as the leading contributors, with 1.3-fold more publications than the combined all of the next top 10 countries. The United States emerges as a clear leader in this domain, contributing the highest number of publications. This leadership position likely results from a combination of robust funding mechanisms, evidenced by the most significant financial support for research and a strong emphasis on medical research and development, evidenced by its central role in the international collaboration network.

Analogous to the geographic distribution, the leading 10 institutions with the highest publication output are primarily located in the United States. National Eye Institution, Johns Hopkins University, Harvard Medical School and the Duke University, the best scientific research institutions in the United States, occupy 4 of the top 10 slots in the list of most prolific institutions. The NEI emerges as a prominent leader in this realm, with the highest publication count. Its leading position, coupled with the highest centrality score of 0.13, not only underscores its prolific output but also its central role in fostering collaborative research efforts. The NEI’s influence in the field is indicative of its commitment to advancing our understanding of AMD, especially in relation to inflammation. Furthermore, the active international cooperation between various institutions underscores the significance of collaboration in fostering growth within this field.

Identifying influential scholars in a particular field provides early-career researchers with insightful guidance and direction. In the data presented in Figure 4 and enumerated in Table 3, we highlighted the authors with the highest number of publications. Kaarniranta from Department of Ophthalmology, Institute of Clinical Medicine, and University of Eastern Finland leads the list with 52 articles and an average citation count of 51.55 per paper. The work of Kaarniranta in the field of AMD represents a significant contribution to our understanding of the disease’s pathogenesis, particularly in relation to the role of inflammation. Kaarniranta’s research delves deeply into the complex mechanisms at play in AMD, emphasizing the critical role of oxidative stress, mitochondrial function, angiogenesis and autophagy, and their interplay with inflammation in the degeneration of the RPE, which opens up new pathways for research and potential therapeutic strategies for AMD.^[22–25]

Kauppinen, Anu as the second most prolific author in this field, also made substantial contribution to unraveling the intricacies of inflammatory processes in AMD. Kauppinen’s work, often in collaboration with Kaarniranta, has been instrumental in deepening the understanding of how inflammation interacts with other cellular mechanisms, such as oxidative stress and autophagy, in the context of AMD.^[5,25–30] This collaboration likely facilitates a more comprehensive exploration of AMD pathogenesis, considering various interconnected pathways that contribute to the disease.

As for the co-cited authors shown in Figure 5 and Table 4, Klein, Ronald from the Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison and Johanna Seddon from Department of Ophthalmology, Tufts University School of Medicine, have published several highly cited review papers on AMD.^[31–34] These review articles help other scholars quickly and accurately understand the field of pathogenesis of AMD. In short, the top 10 authors with the most influential publications and the most co-citations have been leading the entire discipline forward.

Journals are an important vector for the dissemination of academic research results. We summarized the co-citation visualization network of the most influential journals in the field of inflammation in AMD, making it easier for researchers to choose the most suitable journals to submit papers. As shown in Figure 6 and Table 5, Investigative Ophthalmology and Visual Science, Plos One, Experimental Eye Research, International Journal of Molecular Science and Retina-Journal of Retinal and Vitreous Diseases take up the top 5 positions.

Investigative Ophthalmology and Visual Science, leading with the highest number of publications in this domain, is renowned for its comprehensive coverage of all aspects of ophthalmology and visual science. This journal’s focus on cutting-edge research in ocular diseases, mechanisms of visual function, and sight preservation aligns seamlessly with the evolving landscape of AMD research.^[35,36] The substantial number of papers published in IOVS on inflammation in AMD highlights its importance as a central repository of high-impact research findings. It is a testament to the journal’s reputation and influence that researchers prioritize it for submissions of significant studies, which, in turn, propels advancements in understanding and potentially managing AMD.

On the other hand, Experimental Eye Research offers a unique blend of experimental and investigative studies focused on the eye and vision science. Its emphasis on the molecular, cellular, and physiological mechanisms underlying eye diseases makes it an invaluable resource for researchers exploring the complex interplay between inflammation and AMD.^[37] The journal’s commitment to publishing studies that elucidate the pathophysiological processes at play in AMD, including oxidative stress, mitochondrial dysfunction, and autophagy,^[37–39] provides critical insights that bridge basic science with potential therapeutic applications.

The analysis of the top co-cited references in the context of inflammation and AMD underscores the pivotal discoveries and critical shifts in the understanding of AMD’s pathogenesis. The leading 3 articles, as highlighted in Table 7, collectively emphasize the significant role of the complement system in AMD and the global disease burden.

Klein’s study published on Science, with the highest co-citation count, marks a cornerstone in AMD research by identifying the association between CFH polymorphism and AMD. The revelation that genetic variations in CFH, a regulator of the complement pathway, could significantly increase AMD risk highlighted the integral role of the immune system, particularly the complement cascade, in AMD pathogenesis.^[18] This discovery prompted a paradigm shift towards understanding AMD not just as a degenerative condition but as one with a strong inflammatory component.

Published concurrently with Klein’s study, Edwards’s work further cemented the genetic link between CFH polymorphism and AMD.^[16] The slightly lower co-citation count compared to Klein’s article does not diminish its importance; rather, it underscores the collaborative emergence of evidence pointing to the complement system’s dysfunction as a critical factor in AMD. These parallel findings have significantly influenced subsequent research directions, focusing on unraveling the mechanisms by which the complement system contributes to AMD.

The third most co-cited paper was a systematic review article by Wong WL. This publication shifts the focus from molecular mechanisms to the epidemiological aspect of AMD, providing a comprehensive analysis of its global prevalence. By projecting the disease burden into future decades, Wong’s study underscores the pressing need for targeted research and effective public health strategies to manage AMD, highlighting its status as a major global health concern.^[1] This work serves as a call to action for the research community to prioritize AMD due to its significant impact on the aging population.

The analysis of citation bursts, as listed in Figure 7, provides insight into the articles that have significantly influenced the field of AMD research over a specific period. The leading 3 articles, as identified, mark pivotal shifts in our understanding of AMD, particularly emphasizing the roles of inflammation and genetic predispositions in its pathogenesis.

Kauppinen’s 2016 publication stands at the forefront with the strongest citation burst, indicating its profound impact on the field. This article synthesized existing knowledge and presented a compelling argument for the central role of inflammation in AMD.^[5] It meticulously outlined how chronic inflammation acted as both a consequence and a driver of AMD progression, bridging the gap between basic inflammatory mechanisms and clinical manifestations of the disease. By consolidating evidence on various inflammatory markers, pathways, and the interactions between innate and adaptive immunity in AMD, Kauppinen’s work has significantly shaped subsequent research directions, focusing on inflammation as a therapeutic target.

The second most cited burst reference is Klein’s seminal work in 2005 provided the first genetic link between CFH polymorphism and AMD, marking a breakthrough in our understanding of the disease’s genetic underpinnings.^[18] Published in the same year as Klein’s study, Haines’s article further solidified the link between CFH variants and AMD.^[17] The joint contributions of Klein and Haines have fundamentally altered our understanding of AMD, establishing a genetic and inflammatory basis for the disease. Their work has not only elucidated key aspects of AMD pathogenesis but also opened new avenues for research and treatment, emphasizing the importance of the complement system in AMD.

The comprehensive analysis of author keywords and thematic evolution in the domain of inflammation in AMD, as illustrated in Figure 8, provides a panoramic view of the current hot topics and hints at future research trends within this critical area of study. Our findings underscore the dynamic nature of AMD research, highlighting the shift towards exploring intricate mechanisms like oxidative stress, leukocytes (macrophage and microglia) activity, and autophagy in recent years.

It is important to note that the research foci and mechanistic insights discussed below are inferred from bibliometric trends − such as keyword frequency, citation bursts, and thematic evolution − rather than derived from direct experimental evidence within this study. These trends reflect the collective focus of the research community and suggest promising avenues for future experimental validation

All bibliometric analyses, including this study on inflammation in AMD, carry inherent limitations. Firstly, our dataset was exclusively derived from the WoSCC, a common yet selective source for bibliometric studies. This focus means relevant articles available in other databases (e.g., Scopus, PubMed) or published in languages other than English might not have been included, potentially skewing the breadth of our analysis. Furthermore, our analysis is subject to citation bias, wherein highly cited publications may disproportionately influence trends, potentially overlooking emerging or niche research. Additionally, our reliance on bibliometric software, which employs machine learning algorithms for data analysis, introduces a risk of analytical bias due to algorithmic limitations or interpretative errors. Another limitation stems from the publication delay inherent to academic research; new studies continuously emerge, and those published close to our analysis cutoff date may not have been included. This time lag means our study may miss the latest advancements or shifts in research focus within the AMD field, particularly concerning inflammation’s role.

Despite these constraints, our investigation endeavors to provide a comprehensive and systematic overview of the prevailing research trends, key contributors, and future directions within the inflammation in AMD domain. By mapping the landscape of this critical area of AMD research, we aim to furnish researchers with valuable insights, fostering further inquiry and potential collaborations in understanding and addressing this complex condition.