Neurodegenerative diseases (NDs) are heterogeneous diseases that are closely related to aging, the chronic progressive neuronal death eventually leads to the loss of structure and function in specific brain regions (Ellis and Fell, 2017; Jellinger, 2010; Kim et al., 2015). With the trend of global population aging, the number of patients with NDs like Alzheimer’s disease and Parkinson’s disease is rising yearly (Behl, 2021; Manes, 2016; Tzvetkov and Atanasov, 2018). In addition, the incidence of multiple sclerosis, stroke-induced secondary neurodegeneration, Huntington’s disease, human immunodeficiency virus-related neurocognitive impairment, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, and are also growing yearly, bringing huge economic burden (Yeung et al., 2021).

Microglia are considered to be the main driving cells leading to neuronal damage in NDs (Song and Suk, 2017; Spittau, 2017). Overactivation and imbalance of microglia may lead to catastrophic and progressive neurotoxic reactions (Kim and Joh, 2006; Mcgeer et al., 2006; Zecca et al., 2006). However, the mechanism of neurotoxic activation of microglia remains unknown. In addition, microglia will continue to be activated under the stimulation of harmful factors for a long time (Španić et al., 2019). Furthermore, whether microglia phagocytosis is beneficial or harmful remains controversial, most researchers tend to support the beneficial role (Weldon et al., 1998; Ito et al., 2007; Sierra et al., 2010).

Although the role of microglia in NDs is still elusive, it was found that microglia participate in not only the development and maintenance of central nervous system homeostasis but also in the progress of NDs, especially in Alzheimer’s disease. It is of great significance to investigate the interaction between microglia and neurons and the specific mechanism of microglia in the regulation of neural circuits (Bisht et al., 2016; Delpech et al., 2016; Matcovitch-Natan et al., 2016; Nelson et al., 2017), thus it is necessary to find the most influential original research in this field.

By designing this bibliometric and visualized study, we retrieved and screened the highly cited original articles that focused on the role of microglia in NDs in the past 40 years, a bibliometric and visualized study was performed to reveal the trends of publications and citations, highly cited authors, institutions, countries, journals, as well as the hotspots in this field.

This bibliometric and visualized study identified and analyzed the top 100 highly cited articles focusing on the role of microglia and NDs, to our knowledge, we first analyzed the top-cited articles within the field using a bibliometric method and presented some interesting and useful conclusions. Revealing the highly cited authors, institutions, and countries help readers quickly locate the most productive and influential contributors. It must be emphasized that the citations can not fully represent the real academic values, “highly cited”were not equal to “influential”, the impact should be evaluated comprehensively. Even though the representative value of the extracted hotspots from 100 articles is limited, the results of this study can still answer the following questions: What are the highly cited articles mainly focused on? what may be the hotspots in this research field?

The limitations of the study design must be clarified. This is a citation-based bibliometric analysis, most of the results were conducted via visualized analysis, the standard of the evaluation was sole and the results may not be very persuasive. The academic value of an article should be comprehensively evaluated, except for the cited times, the contribution to the field, whether it added new to the existing knowledge, whether it can guide the clinical management of the diseases should be considered. Besides, the impact factors, h-index, reputations, and rate of self-citation of journals should be considered. We analyzed the author keywords by the co-occurrence analysis and burst of keywords, the detailed research topics and key points of these articles were not retracted. Due to the limited number of author keywords, the burst detection and timeline map of keywords may not represent the real hotspots. Furthermore, the total citations can be significantly influenced by the age of literature, which may lead to bias when screening highly cited articles. Despite these shortcomings, citation analysis is the most widely used and subjective method in bibliometric analysis.

The peak of publications of the highly cited articles was during the first decade of the 21st century, indicating that the period was the golden years of highly cited microglia research. The citation of 2021 was not shown on the map because it has not been fully counted and the results can not represent the real trend. It must be emphasized that the total cited times of articles that were published after the 2010s can be underestimated, to balance the citations and age of literature, we introduced citation density to evaluate the average citations yearly. The results showed that the citation densities raised yearly, articles with high citation density frequently occurred after 2010, articles with the highest citation densities frequently appeared in the recent 5 years, indicating that recently published articles were more prone to be cited. In terms of yearly total citations, the number of yearly citations quickly raised since 2015, suggesting that the number of original research greatly boomed in recent 7 years. The citation number of 2021 was not presented in the trend map because it has not been fully counted.

The United States had the largest record counts among the top 100 cited articles, which owns the overwhelming number of citations and record counts, indicating that the United States was the most productive and influential country in this field. With the aging of the global population, the burden of NDs is increasing yearly (Chee and Solito, 2021). In the United States, Alzheimer’s disease affected five million people and caused a huge amount of healthcare costs (Hurd et al., 2013), it has been predicted that the number of dementia in the United States will increase by 35% by 2030 (Petersen et al., 2018). Parkinson’s disease has been reported with the prevalence of 4% in men and 2% in women in the 85 years old North American population (Marras et al., 2018). Multiple sclerosis affects 2–3 million people globally (Browne et al., 2014) (Vaughn et al., 2019), especially minorities in the United States (Ventura et al., 2017; Wallin et al., 2019). The United States owns the largest number of famous universities and leads the tide of neurodegenerative research around the world. We found that nearly all of the top 10 highly cited institutions belong to the United States (9/10). More than half of the highly cited authors were from the United States (7/10), more than half of the most frequently cited authors in the references were from the United States (6/10). Harvard University was the institution with overwhelming cited times among all institutions, reflecting its authority in the field of microglia and NDs.

The top-cited articles were most often published in top journals within the research field, including Nature, Science, and Cell, as well as the authoritative journals in the field of neuroscience, including the Journal of Neuroscience, Nature Neuroscience, Nature Medicine, and Glia, suggesting that these journals mostly tend to publish original research in microglia and NDs. The distribution of highly cited journals in the references was similar to the published journals. It’s worth noting that the Journal of Neuroscience, though has a lower impact factor compared to these top journals, was both the largest publisher and the most frequently cited journals in the references, suggesting its authority in this field. The impact factor of one journal was calculated by citations and the number of published articles, however, it should not be considered as the most important standard when evaluating the academic value of journals. Revealing the highly cited journals help readers quickly locate the most often published and cited publishers in this field, which can be a reference when submitting their papers and retrieving the literature.

The hotspots were extracted by co-occurrence analysis and burst detection of author keywords. The Citespace software, developed by Doctor Chaomei Chen (Chen et al., 2012), was widely used in the bibliometric analysis, especially famous for its burst detection function. The results showed that the most interesting NDs were Alzheimer’s Disease, followed by Parkinson’s Disease, the third was Multiple Sclerosis, the trend was consistent with the morbidity and global epidemiology of NDs. Keywords that described the symptom of Alzheimer’s disease were most frequently used, suggesting that Alzheimer’s disease was the hotspot in the research of NDs. The microglia was the main inflammatory cell during the pathogenesis and development of NDs (Yeung et al., 2017). Not surprisingly, the original research most frequently focused on inflammation, and the keywords related to inflammations burst in recent years.

To emphasize the clinical guiding significance, original clinical research was also included for analysis. Besides, we extracted and listed the top 10 cited reviews in this field (not among the top 100 articles) and summarized their major topics (Supplementary Table 2). Among the top 10 most cited reviews, five of them were from the United States, they focused on the mechanism of neuroinflammation in Alzheimer’s disease (Akiyama et al., 2000), neurotoxicity mediated by microglia in NDs (Block et al., 2007), oxidative stress (Andersen, 2004), and molecular mechanism of blood-brain barrier damage (Zlokovic, 2008). In two reviews from England, the authors investigated the interaction between microglia and oligodendrocytes and the mechanism of microglia in neuroinflammatory demyelination in multiple sclerosis (Fawcett and Asher, 1999; Compston and Coles, 2008). Two reviews from Germany discussed the mechanism of neuroinflammation in Alzheimer’s disease and the specific pathway of glutathione, an important factor of oxidative stress in the nervous system (Dringen, 2000; Heneka et al., 2015). One review summarized the detailed process of neuroinflammatory response in Parkinson’s disease and preliminarily presented the research progress and future research direction of targeting microglial inflammatory factors to alleviate the clinical symptoms of Parkinson’s disease (Hirsch and Hunot, 2009). Though the highly cited reviews were not included for analysis in this study, they represent the currently most focused topics in the field of microglia and NDs. Regarding the epidemiology of the NDs, the incidence of Alzheimer’s disease, dementia, and cognitive impairment is increasing yearly. Previous studies have confirmed the toxic effect of microglial inflammation on neurons. Therefore, it is a general trend to clarify the role of microglia in dementia.

Regarding the mechanisms, activated microglia continuously secrete inflammatory factors and reactive oxygen species to attack neurons, resulting in neuronal damage (Fiebich et al., 2014; Španić et al., 2019). Microglia may also respond to demyelination of oligodendrocyte precursor cells by phagocytosis of myelin fragments, remodeling extracellular matrix and secreting nutritional factors needed by oligodendrocytes, and promoting the process of neuronal extubation and remyelination (Tay et al., 2017). In addition, microglia have a Toll-like Receptor on the surface, which can effectively mediate antigen recognition (Schetters et al., 2017). Activated microglia also have a lysosomal mechanism, which helps antigens recognize and express MHC-class II costimulatory molecules (Verkhratsky et al., 2021) needed to present myelin antigen peptides to central nervous system antigen-specific CD4⁺ T cells. The mechanisms were not the main purpose of this bibliometric analysis, but it still helps readers better understand the current research trends.

Inflammatory demyelination and neuronal degeneration are the main pathological changes of multiple sclerosis. Microglia is crucial in this pathological change, neuroinflammation is the hot area in the current research, which is consistent with the major conclusion of this study. In short, microglia mainly participate in the process of oxidative stress and antigen presentation, which affect the permeability and integrity of the blood–brain barrier, and eventually lead to the disorder of the immune internal environment of the central nervous system. Therefore, microglia may have different phenotypes, functions, and states under different pathological stimuli, but whether their effects are pathogenic or protective, or both, is controversial (Prinz et al., 2011).

The development of single-cell sequencing and genomics techniques has further enabled the classification and identification of microglia from phagocytes of other sources, which is conducive to the development of targeted drugs for microglia (Miron et al., 2013). Some experimental studies revealed that macrophages have a certain effect on myelin regeneration, but the specific process is not clear and needs further research (Ruckh et al., 2012; Sominsky et al., 2018). For clinicians, gathering top-cited articles may contribute to the clinical transformation of the basic research of diagnosis, clinical decision-making, as well as explore the diagnostic markers of clinical diseases and drugs targeting specific phenotypic functions of microglia.

The bibliometric analysis and visualized study have some limitations. First, the retrieve of literature was based on the WOS website only, the representative value of extracted results was limited. Second, this is a citation-based bibliometric analysis, the screening of articles, rank of authors, institutions, journals, and countries was mostly based on total cited times, the “highly cited” are not equal to “influential,” thus the conclusion can be not very persuasive. Furthermore, the citations can be significantly influenced by age of literature, articles published recently may be missed though they have high academic value. Third, the hotspots that were extracted from keywords may not represent the real research interests because the number of total keywords was small. Fourth, the bibliometric analysis mainly focused on quantitatively analyzing the characteristics of the literature, the detailed context of these articles were not fully investigated and summarized, as a result, the conclusions were superficial. Fifth, the majority of articles included in this study were experimental research, we aimed to reveal the trend in the original research, though clinical articles were included and top-cited reviews were discussed, limited useful information can be gathered by clinicians.

This bibliometric and visualized analysis investigated the 100 top-cited original studies concentrated on the role of microglia in NDs. Revealing the highly cited articles help readers quickly locate the most productive and influential contributors, as well as gather the hotspots and latest trend in this field. The United States was the biggest contributor, Harford University was the most influential institution. Journal of Neuroscience was the most often published and cited journal. Alzheimer’s disease was the hotspot of microglia-related study. The recent research mainly focused on inflammation.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

MS and XL: conceptualization and writing of the original draft. JS: data curation. HW: software. QX: conceptualization and writing—review and editing; MW: conceptualization and project administration. All authors contributed to the article and approved the submitted version.

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.