Research Trends in the Comorbidity Between Periodontitis and Neurodegenerative Diseases

Abstract

Introduction and aims

Evidence suggests an association between periodontitis and neurodegenerative diseases, but a comprehensive analysis of research trends remains absent. Therefore, we aim to identify research trends and hotspots on the comorbidity between periodontitis and neurodegenerative diseases, understand mechanisms, provide guidance for subsequent studies and show its clinical translational possibility.

Methods

A bibliometric analysis covering 1982 to 2023 was conducted using the Web of Science Core Collection. English-language articles range from January 1, 1982 to November 30, 2023 were analyzed. Data were downloaded on November 30, 2023 and analyzed on December, 2023. Data visualization and statistical analysis were performed to identify trends of annual publications, countries, sources, institutions, authors, most cited articles, and keywords by using Microsoft Excel, VOSviewer, Citespace, R-bibliometrix and Origin Pro.

Results

A total of 1,238 articles from 1982 to 2023 on the comorbidity between periodontitis and neurodegenerative diseases were identified. Annual publications showed an upward trend. The United States, University College of London, BRAIN and Shy, Michael E. were the leading nation, affiliation, source and author, respectively. The United States, NEUROLOGY, and Curtis Maurice A. were the most cited nation, source, and author. Keywords network analysis highlighted 'Charcot-Marie-Tooth Disease', 'Alzheimer's Disease' and 'Periodontitis' as focal points. Detection of keywords citation bursts demonstrated 'Porphyromonas gingivalis' and 'Cognitive Dysfunction' as hot topics in recent research.

Conclusions

In recent years, emerging interests of the comorbidity between periodontitis and neurodegenerative diseases (NDs) are growing. Our study enhances the understanding of recent research trends of periodontitis and NDs and provides valuable perspectives within this expanding field, offering new insights into research trends regarding the interplay between 'Porphyromonas gingivalis' and 'Cognitive Dysfunction'. Further research of the molecular mechanisms between P. gingivalis-induced periodontitis, neuroinflammation, that leads neurodegeneration are clearly warranted.

Introduction

Periodontitis, characterized by a progressive breakdown of the attachment apparatus of teeth, ultimately resulting in tooth loss and occlusal dysfunction, is a chronic inflammatory disease of high prevalence.¹ In recent decades, a growing body of evidence has demonstrated the correlation between periodontitis and systemic conditions, including but not limited to diabetes mellitus, cardiovascular diseases, renal diseases.² Among the myriad systemic diseases potentially influenced by periodontitis, a compelling area of research has emerged regarding the comorbidity between periodontitis and neurodegenerative diseases (NDs). There are shared risk factors on the progression of periodontitis and NDs, such as gender, age, and so on.^3,4 Indeed, the comorbidity between periodontitis and NDs can be observed through direct and indirect pathways, including bacterial re-colonization, systemic inflammatory responses, chronic inflammation and other unknown mechanisms. These elements are potential initiators of neuroinflammation and neurodegeneration, playing crucial roles in the onset and advancement of neurodegenerative disorders, periodontitis and systemic diseases.5, 6, 7, 8, 9 Moreover, patients with periodontitis are at higher odds in developing Alzheimer's Disease (AD).¹⁰ In addition, it has been shown effective to prevent Parkinson's Disease (PD) and dementia by eradicating periodontitis-related pathogens and applying aggressive treatment.¹¹

This intersection heralds a promising era for interdisciplinary research bridging Stomatology and Neurology, as the oral cavity potentially reflects neurological health. Understanding the pathophysiology of NDs opens new avenues for innovative oral disease treatments. Therefore, a deeper exploration into the complexities between these two fields is essential for a comprehensive analysis of the relevant research trends.

Bibliometric analysis is a scientific discipline dedicated to evaluating and quantifying various aspects of specific fields. It assesses the productivity of countries, authors, affiliations, and other relevant factors.¹² To the best of our knowledge, no comprehensive studies have analyzed the research trends in the comorbidity between periodontitis and NDs. Therefore, bibliometric analysis can serve as a navigator by providing references to trends, contributions and academic hotspots in the field.

Herein, we performed a bibliometric analysis to explore the overarching research trends and hotspots related to the comorbidity between periodontitis and NDs, aimed to provide anticipatory guidance for future research directions.

Materials and methods

Data source and search strategy

Relevant data were extracted from the Science Citation Index Expanded (SCI-Expanded) of the Web of Science Core Collection (WoSCC). The search terms were centered on periodontitis and NDs guided by the MeSH & entry terms listed in Pubmed MeSH database, along with additional keywords identified in other articles. The search formula (in brief) was: TS = ('Periodontitis' OR 'Porphyromonas gingivalis' OR 'Tooth loss' OR 'Occlusal Dysfunction') And TS = ('Alzheimer Disease' OR 'Alzheimer's Disease' OR 'AD' OR 'Dementia' OR 'Amyotrophic Latera Sclerosis' OR 'Gehrig* Disease' OR 'Charcot Disease' OR 'ALS' OR 'Parkinson Disease' OR 'Parkinson's Disease' OR 'Paralysis Agitans' OR 'PD' OR 'Huntington's Disease' OR 'Huntington Disease' OR 'Huntington Chorea' OR 'HD' OR 'Cognitive Dysfunction' OR 'Neurodegeneration'). A total of 1,238 articles were retrieved. The primary literatures selected for our study were articles, and the language was limited to English. The time span was ranged from 1982 (January 1, 1982, the first year to have relevant publications) to 2023 (November 30, 2023). The schematic progress of the data collection and analysis has been illustrated below (Figure 1).

Fig. 1.

Schematic representation of data collection and analysis progress. Abbreviations: NDs, Neurodegenerative Diseases; AD, Alzheimer's Disease; PD, Parkinson's Disease; HD, Huntington Disease; ALS, Amyotrophic Latera Sclerosis.

Data validation and statistical analysis

Data were analyzed in December, 2023. All data analyses and statistical testing were performed using Microsoft Excel, VOSviewer version 1.6.20, Citespace version 6.2.6 and R-Bibliometrix version 4.3.1, Origin Pro 2024.

Microsoft Excel was primarily utilized to consolidate synonymous terms in the keywords list, eliminate duplications, and standardize the expression of keywords, thereby enhancing the precision and quality of keywords analysis. Statistical tables were created using Excel.

VOSviewer is a software designed to represent large bibliometric maps in an easily interpretable manner.¹³ In the visualization maps, nodes represent specific authors, institutions, and keywords, with scales and sizes indicating the number of publications (NP) authored by individuals or organizations, or the occurrences of keywords. Total link strength (TLS) is an element indicating connections which is demonstrated via lines between nodes. Various colors categorize distinct clusters. In the overlay maps, colors are arranged in a spectrum from blue through green to yellow, based on the average publication year (APY) of articles. Therefore, VOSviewer was employed to visually illustrate contributions and collaborative relationships among countries, authors and research keywords within the domain of the comorbidity involving periodontitis and NDs. To emphasize hot keywords and enhance aesthetics, we manually adjusted shapes of the maps by manipulating the coordinates.

The R-bibliometrix facilitated exploring the characteristics and patterns within the publications and was used to obtain information on annual publications, country distribution, authors, institutions, most cited sources and articles.

The CiteSpace excel at detecting strongest citation bursts of keywords, aiding in monitoring the transition of research hotspots over time and predicting future developments in the field. Therefore, this feature was employed to identify bursts in keyword citations.

Origin Pro, featuring in abundant graph choices for visualization, was used in generating statistics and enhancing image beautification.

Risk of bias (quality) assessment

Three researchers participated in this process. Two researchers independently extracted keywords from the final set of articles and got the same number of keywords. Subsequently, these two researchers identified synonymous terms and standardized expressions using the PubMed MeSH database, respectively, and jointly carried out the final analysis of this study. Upon reaching an agreement on the final expression of the terms, they independently made revisions and removed duplicates. In cases of discrepancies between the results of these two researchers, the third researcher was consulted for a final decision.

Results

A total of 1,238 articles were retrieved from the data. 60 articles are in-vivo studies and 68 are in-vitro studies. 309 articles are animal studies and 97 are human studies.

Trends of annual publications

A total of 1,238 articles in total published from 1982 to 2023 were identified. The evolving publication count on the topic of the comorbidity between periodontitis and NDs was visually depicted (Figure 2A). Overall, the number of publications (blue columns) ranged from 1 (in 1982) to 118 (in 2023), showing a general increasing trends despite some fluctuations. This upward trends in publications signifies the connections between periodontitis and NDs, reflecting the dynamic nature and growing relevance of this research field. Meanwhile, the number of total citations (orange line) topped 4,764 in 2021 and ended with 4,388 in 2023, which was also an robust evidence for the increasing trend of this domain in the aspect of citations.

Fig. 2.

Analysis of publications, citations, countries and journals. (A) Trends of annual publications and total citations regarding the comorbidity between periodontitis and NDs through years; (B) Publications among countries; (C) Map of multinational collaborations. Brown lines between countries show the link strength between countries; (D) Map and table of international collaboration work; (E) Distribution of corresponding author's countries; (F) Top 10 most local cited journals.

Analysis of countries/nations

Distribution of publications among countries

Total 72 countries globally contributed to publications in this study, where USA (275; 22.2%), China (168; 13.6%), and Japan (160; 12.9%) were emerging as the top three contributors (eTable 1). Notably, the USA standed out with the highest number of citations (13,808) and with an average citations of 50.2, second to the United Kingdom (57.7). The United States, China and Japan were highlighted by columns in dark red, showcasing a prominent distribution of publication count in these top 3 nations, collectively generating nearly half of the publications in total (Figure 2B).

Collaboration of countries’ publications

Seventy-two countries participate in publications in this study. The USA was closely linked with European countries and emerged as the most prolific country (Figure 2C). The collaboration network highlighted that the most frequent partnerships involved USA and England, followed by collaborations with China, Italy and Germany (Figure 2D). Additionally, the multiple country publication ratio (MCP ratio) indicated robust international collaborations (eTable 1). Within the top 5 countries of publication, the United Kingdom emerged as the leader in multinational partnerships, boasting the highest MCP ratio of 0.459. To enhance clarity, the MCP ratio highlighted a pronounced inclination for international cooperation among these nations (Figure 2E). A higher MCP ratio signified a greater extent of multinational collaborations, whereas a lower one suggested a comparatively domestic and internal focus.

Analysis of journals/sources

Total 418 journals were included for the analysis. Impact factors (IF) and Journal Impact Factor (JIF) quartiles were acquired from 2022 Journal Citation Reports. The top 10 most relevant sources were ranked by publications (eTable 2). Among the top 10 journals, 7 of them were in Q1 or Q2, demonstrating that these journals enjoyed relatively high scholar reputations in this domain. NEUROLOGY (1,469 citations; IF = 10.1; Q1) was the top most local cited journal of the ten (Figure 2F).

Analysis of authors and institutions

A total of 7,284 authors from 1, 743 institutions contributed to the publications on our topic. The 5 most active authors and institutions have been highlighted (eTable 3). Among the most influential authors, SHY ME (Shy Michael E.) from University of Iowa led with 30 publications, constituting 2.4% of the total, H-index: 61, accumulating 1,966 citations. Following closely were SCHERER SS (Scherer, Steven S.) with 25 publications (2.0%, H-index = 69) and REILLY MM (Reilly, Mary M.) with 24 publications (1.9%, H-index = 61). In terms of institutions, the University College of London exhibited the highest productivity with 125 publications (10.0%), followed by the University of London (120 publications, 9.7%) and the University of Michigan (79 publications, 6.3%). The top 5 most cited authors included CURTIS MA (Curtis, Maurice A.) (232 local citations), STEIN PS (Stein, Paul S.) (199 local citations), KAMER AR (Kamer, A. R.) (195 local citations), SHY ME (Shy Michael E.) (195 local citations) and REYNOLDS EC (Reynolds, Eric C.) (190 local citations) (Figure 3A).

Fig. 3.

Analysis of authors and references. (A) Top 5 most local cited authors; (B) Co-authorship network; (C) Co-authorship overlay map arranged by year; (D) Visualization of most commonly cited references.

The co-author network, comprised 52 authors with a Total Link Strength (TLS) of 484, each contributing to at least 5 articles. Notably, Choi, Byung-ok (TLS: 50), REILLY MM (Reilly, Mary M.) (TLS: 49), and Pareyson, Davide (TLS: 44), exhibited the strongest collaborations with others (Figure 3B). Choi, Byung-ok (APY: 2018.00; NP: 19; TLS: 50) and Nam, Soo hyun (APY: 2018.90; NP: 10; TLS: 36) prominently standed out in yellow, who published the most on this topic in recent years (Figure 3C).

Analysis of articles

Table 1 displayed 10 articles with the highest citations in the field, for which the number of citations ranged from 342 to 901, signifying their frequent reference in subsequent research, thereby underscoring the widespread acknowledgment and significance of them within the research domain (Table 1).

Table 1.

Top 10 most cited articles.

Rank	Author and year	Title	Journal (IF-22)	TC	TC/Y
1	DOMINY SS, 2019	Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors14	SCI ADV (13.6 Q1)	901	180.20
2	CHEN HC, 2007	Mitochondrial Fusion Protects against Neurodegeneration in the Cerebellum15	CELL (64.5 Q1)	682	40.12
3	ZHAO C, 2001	Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bβ16	CELL (64.5 Q1)	570	24.78
4	PETZOLD A, 2005	Neurofilament phosphoforms: Surrogate markers for axonal injury, degeneration and loss17	J NEUROL SCI (4.4 Q2)	493	25.95
5	MISKO A, 2010	Mitofusin 2 Is Necessary for Transport of Axonal Mitochondria and Interacts with the Miro/Milton Complex18	J NEUROL SCI (4.4 Q2)	448	32.00
6	DE SANDRE-GIOVANNOLI A, 2002	Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse19	AM J HUM GENET (9.8 Q1)	412	18.73
7	YU-WAI-MAN P, 2011	Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies20	PROG RETIN EYE RES (17.8 Q1)	405	31.15
8	NICOLAS A, 2018	Genome-wide Analyses Identify KIF5A as a Novel ALS Gene21	NEURON (16.2 Q1)	378	63.00
9	CHOW CY, 2007	Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J22	NATURE (64.8 Q1)	372	21.88
10	PICH S, 2005	The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system23	HUM MOL GENET (3.5 Q3)	342	18.00

Significantly, six of these top articles whose IF surpassed 10 were published in Q1 journals, demonstrating the significance of influential publications in the field. Given that articles in Q1 journals are commonly with high IF, this results may be a possible reflection of their quality. As to the most frequently cited references, DOMINY SS (2019) ranked first in the list (Figure 3D).

Analysis of keywords

Keywords co-occurrence networks

After excluding duplications and replacing similar paraphrases with formal terms manually using Microsoft Excel, 42 related keywords occurred more than 15 times among the 4,846 keywords extracted from the 1,238 articles. 'CMT' (372), 'AD' (298) and 'Periodontitis' (269) were the most frequent keywords. These keywords were then categorized into three clusters, each represented by a different color.

Cluster 1 (red color) primarily provided information about factors and the progression of CMT (Charcot-Marie-Tooth Disease), highlighting 'CMT', 'mutations' and 'neuropathy'. It also encompassed epigenetic mechanisms like 'myelination', 'axonal degeneration', 'genes' (such as 'PMP22′ and 'GDAP1′), 'proteins' (such as 'MFN2′ and 'connexin 32′), 'mitochondria', and cell components like 'Schwann cells'. Understanding these elements may be crucial for unraveling the mechanisms behind these disorders and exploring potential therapeutic interventions. Cluster 2 (green color) included various elements related to central NDs, particularly 'AD' and 'PD', with a focus on the most related oral disease 'Periodontitis', as well as factors such as 'Porphyromonas gingivalis', 'inflammation' and 'neurodegeneration'. Exploring these connections contributes to a broader understanding of comorbidities among central degenerative diseases and oral health and provides novel research ideas for therapeutic approaches. Cluster 3 (blue color) involved cognitive and oral conditions such as 'dementia', 'cognitive dysfunction' and 'tooth loss' (Figure 4A). It suggested an interconnection between cognitive health and oral well-being, indicating that cognitive dysfunction may impact oral health practices, including tooth loss.

Fig. 4.

Analysis of keywords. (A) Co-occurrence keywords network; (B) Co-occurrence overlay map arranged by year; (C) The top 10 keywords with the strongest citation bursts from 2013 to 2023 sorted by the beginning years. Lines in red illustrate the evolution of keyword occurrence from its inception to its establishment. Periods marked by comparatively lower citations of the keywords are denoted by lines in green. Abbreviations: AD, Alzheimer's Disease; CMT, Charcot-Marie-Tooth Disease; PD, Parkinson's Disease.

The overlay map of keywords by year revealed that the most recently studied topics (in light green & yellow color) are 'Periodontitis', 'AD' and 'PD' (Figure 4B). This suggested an increasing interest in the comorbidity between periodontitis and NDs. Additionally, there was a noticeable uptick in research on the neuroinflammation caused by Porphyromonas gingivalis (the primary pathogenic bacteria in periodontitis), as these 2 terms were highlighted in yellow. Moreover, the figure indicated a growing focus on Aβ, lipopolysaccharide and microglia, indicating potential research hotspots of periodontitis and NDs in future studies.

Citation bursts of keywords

The recent shift in research priorities is evident from the increased emphasis on keywords such as ‘Porphyromonas gingivalis’ (2021-2023) and ‘cognitive dysfunction’ (2021-2023) (Figure 4C). The heightened focus on ‘Porphyromonas gingivalis’ signifies a noteworthy exploration of the potential role of this bacterium, a key pathogen in periodontitis linked to various systemic pathologies, including NDs.²⁴ The term 'cognitive dysfunction' implies outcomes that may be influenced by periodontitis,²⁵ indicating a research focus on unfolding the intricate connections between periodontal health and neurodegenerative disorders. Moreover, the topics of ‘systemic inflammation’ (2019-2020), ‘Parkinson disease’ (2020-2021) and ‘mitofusin 2’ (2014-2017) have attended considerable interests, indicating an increasing understanding of the immune system, NDs, and potential epigenetic mechanisms in the context of periodontitis and NDs.

Discussion

In the past few decades, research on the comorbidity between periodontitis and NDs has gradually increased, highlighting the ongoing progress in biomedical research and underscoring the potential for interdisciplinary study.

First of all, our analysis reveals that several countries have made significant contributions in this area. The United States, China, and Japan stand out as the most prolific in publication volume. This phenomenon could be attributed to the increasing number of aging populations in these countries, given the known correlation between aging and both NDs and periodontitis.^26,27 Another factor could be the robust research capabilities and high scientific standards in these countries, thus providing excellent platforms for institutions and authors. Moreover, the visualization of the map reveals collaborative relationships among countries, particularly between the United States and various European countries. This collaboration suggests a global endeavor to better understand the connections between periodontitis, NDs and associated comorbidities.

Secondly, our research identifies BRAIN, HUMAN MOLECULAR GENETICS and JOURNAL OF ALZHEIMERS DISEASE as journals with the greatest impact on this field. Surprisingly, within the leading 10 journals, there are not only those focused on Neuroscience but also journals from Molecular Biology, Genetics, Dentistry and other fields. This distribution may suggest the interdisciplinary character of research within this field, transcending singular focus areas. In our analysis of journals and sources, we considered both IF and JIF quartiles to evaluate a journal's reputation, and these two indicators are widely employed in the initial assessment of quality for general medical journals.²⁸ However, it is essential to note that, although examining the productivity of various journals provides a comprehensive perspective on the most prominent sources within the specific field, it might not necessarily provide precise guidance for researchers regarding their resource allocation, as specific study may require tailored analysis.

Next, research institutions in this field are predominantly concentrated in Western nations such as the United Kingdom and the United States, which aligns with the collaboration outcomes observed among countries. University College London emerges as the institution with the highest number of publications in this particular field. Shy Michael E. from University of Iowa stands out as the most prolific author in this field, whose recent study, 'Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J ', has revealed that the accumulation of huge vacuoles exhibiting immunoactivity to LAMP-2 goes parallel with the malfunction of the late endosome-lysosome axis.²² This impairment in the innate immune defense process can consequently result in periodontitis.²⁹ Therefore, this work has a focus on the elementary mechanisms of neuropathology, which lay foundation for subsequent research. After the analyses of authors and institutions, our findings could offer valuable references and collaboration opportunities for future researchers in this field. However, it is important to note that these discoveries only indicate quantity of contributions, which may not represent the caliber or influence of the conducted research for certain. More specific research is needed.

Furthermore, a notable finding in our analyses is an article titled 'Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors' published in 2019, in the Journal of Science-Advanced Materials and Devices, with a current citation count of 901. The article reports that the colonization of Porphyromonas gingivalis in the cerebral tissues of patients diagnosed with AD is implicated in the increased generation of Aβ_1-42 (a component in amyloid plaques). The study also highlights that gingipains, produced by P. gingivalis, may contribute to tau toxicity, affecting normal neuronal function. Furthermore, this research introduced molecular inhibitors targeting gingipains to diminish cerebral infection, decrease Aβ_1-42 generation, alleviate neuroinflammatory responses, and protect neurons in the hippocampus.¹⁴ In summary, the article not only addresses the role of periodontal pathogens in NDs but also introduces novel therapeutic potentials. These factors may explain why it has been most cited in recent years.

In addition, the recent research focus has transitioned from the distinct investigation of oral diseases and neurodegenerative disorders to a more comprehensive perspective, with particular emphasis on P. gingivalis and its potential impact of inflammation on AD in general. Our keyword analysis reveals that literature on the comorbidity between periodontitis and NDs frequently mentions terms such as CMT (Charcot-Marie-Tooth Disease), AD, periodontitis, inflammation, cognitive dysfunction and several molecules like Aβ, Mitofusin 2 and PMP22. CMT is an inherited neurodegenerative disorder associated with potential neuromuscular dysfunction.³⁰ The accumulation of Aβ plaque is a central pathological feature of AD.^31,32 Mitofusin 2, found mutated in CMT, is a mitochondrial dynamin-related protein.³³ The PMP22 gene, responsible for encoding a myelin protein, has been identified within the duplication and been proposed as a candidate gene for CMT.³⁴ These results imply that periodontitis can contribute to inflammation at a systemic level, potentially influencing the development of NDs.¹ Additionally, individuals experiencing cognitive dysfunction like CMT, AD or PD may face challenges in managing oral hygiene, thus adding risk to oral problems.³⁵ Correspondently, the effect of periodontitis on tooth loss or mastication may lead to vitamin D deficiency, which may lead to cognitive dysfunction.²⁵ Moreover, Aβ deposition and mitofusin 2 dysfunction may contribute to the shared pathogenic mechanisms of periodontitis and AD.36, 37, 38 These findings further support our keyword analysis outcomes. However, it is crucial to note that the high frequency of terms alone does not establish their biomedical significance in the disease process. Instead, it indicates active exploration and potential directions in this field. Further research is necessary to validate their roles in the pathogenesis of the diseases and their potential comorbidities.

To investigate the intricate comorbidity between Porphyromonas gingivalis-induced periodontitis and AD, we dissected the underlying mechanisms based on recently published research findings (Figure 5). In a comprehensive scope, the preceding investigations have primarily delved into four dimensions: inflammation, macrophage response, mitochondrial dysfunction and alternations in the hippocampus and brain. Specifically, following infection by P. gingivalis (Porphyromonas gingivalis), oral microbial dysbiosis ensues, initiating the activation of P38 MAPK pathway. This activation is accompanied by heightened expression of interleukin-1beta (IL-1β), interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), C Reactive Protein (CRP), Amyloid Precursor Protein (APP) and Beta-site APP-cleaving Enzyme 1 (BACE1).39, 40, 41 Upon P. gingivalis traversing blood brain barrier, the Major facilitator superfamily domain containing 2a (Mfsd2a) undergoes inhibition, resulting in the downregulation of Caveolin-1 (Cav-1), thereby enhancing the permeability of brain microvascular endothelial cells (BMECs) and facilitating the increased entry of P. gingivalis.⁴² The activated pro-inflammatory cytokines and associated signaling pathways plays a pivotal role in promoting systemic inflammation and neuroinflammation, further heightening the risk of cognitive impairments. Additionally, the abundant expression of msRNA P.G_45033 in P. gingivalis is detected within macrophages, enhancing glycolysis and histone lactylation, consequently inducing the production of Aβ.⁴³ The lipopolysaccharide (LPS) of P. gingivalis contributes to mitochondrial dysfunction through initiating toll-like receptor (TLR) 4 signaling pathway, suppressing oxidative phosphorylation, and inhibiting adenosine triphosphate (ATP) production. This cascade results in oxidative stress and inflammatory events in NDs.⁴⁴ In the advanced stages of P. gingivalis infection, tooth loss ensues as an inevitable outcome. Studies indicate that tooth loss increases the expression of IL-1β, activates the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and elevates Caspase-1 expression in the hippocampus.⁴⁵ Meanwhile, evidence supports that tooth loss induces hippocampal atrophy, diminishes claudin-5 levels, induces astrogliosis in mice brains, leading to learning dysfunction.^46,47 Therefore, these intricate interactions underscore the multifaceted interconnection between periodontitis and AD, emphasizing the necessity for comprehensive understanding and targeted clinical interventions. However, there are relatively few clinical studies on the use of oral microbiome interventions in the treatment of AD or other NDs, but it's worth to mention that some preliminary research interventions targeting the oral microbiome may be beneficial in certain NDs cases.¹⁴

Fig. 5.

Mechanisms of comorbidity between P. gingivalis-induced periodontitis and AD. Abbreviations: P. gingivalis, Porphyromonas gingivalis; Mfsd2a, Major facilitator superfamily domain containing 2a; Cav-1, Caveolin-1; TLR, toll-like receptor; ATP, adenosine triphosphate; NLRP3, NOD-like receptor thermal protein domain associated protein 3; IL, interleukin; TNF, tumor necrosis factor; CRP, C reactive protein; APP, Amyloid Precursor Protein; ↑, increase; ↓, decrease.

The findings of our study hold significant clinical implications and translational potential for dental practitioners and researchers. Firstly, it can be a guidance for future collaborations and information sources. By highlighting productive nations, affiliations, authors, and journals in the field of comorbidity between periodontitis and NDs, our study provides valuable insights for dental practitioners, as they can leverage this information to follow the latest research developments and access high-quality resources to guide their clinical practice. Secondly, it can enhance understanding of disease mechanisms. The identification of hot keywords not only offers references for research focal points but also enriches our understanding of the underlying mechanisms linking periodontitis and NDs. This deeper insight can inform clinical decision-making by enabling dental practitioners to recognize potential connections between oral health and neurological conditions in their patients. Moreover, these analysis can inform therapeutic strategies. The insights gained from our study can guide the development of potential therapeutic strategies for managing both periodontitis and NDs. By understanding the shared pathological mechanisms and emerging research trends, dental practitioners and researchers can explore novel treatment approaches that target common pathways underlying these comorbidities. This could lead to the development of more effective therapeutic interventions aimed at improving patient outcomes and quality of life. In summary, by translating research trends into clinical practice, we can ultimately improve patient care and advance the field of dental medicine in addressing the complex interplay between periodontitis and NDs.

However, limitations of this investigation should not be overlooked. They may include the fact that this study exclusively relies on articles from the WoSCC. While WoSCC is a widely utilized database for bibliometric analysis, we cannot assure the absence of new discoveries in other databases. Additionally, we utilized various analysis softwares, such as VOSviewer, CiteSpace, R-bibliometrix, Origin Pro and manually filtered and merged keywords by a single researcher, which could unintentionally result in loss of data and certain errors by humans in the course of analysis. Nevertheless, there is assurance that these constraints have a minimal effect on the broader patterns within this research domain. Furthermore, while bibliometric analysis excels in quantifying research volume and visualizing trends, it does not discern the quality of the particular studies. Therefore, it should be clarified that our study primarily depicts the quantity and trends of published research on the comorbidity between periodontitis and NDs rather than their quality. This suggests that the particular trends or phrases uncovered in our investigation should not be considered as decisive indicators of their biomedical importance or prominence within the field. Instead, they serve as reference points, shedding light on ongoing research and considerable interest within the scientific community. Finally, the findings of our study are constrained to the publications of the past and present, and their continuation in the future remains uncertain.

Conclusion

A significant increase in studies regarding the comorbidity between periodontitis and NDs has been shown from 1982 to 2023. This research trend emphasizes the substantial contributions from nations such as the United States, China and Japan in this particular domain. Recent studies have also indicated potential correlations between periodontitis, Porphyromonas gingivalis, neuroinflammation and AD providing an important reference for future research directions and clinical translational possibility in this field. After delving into the detailed analyses of countries, journals, authors, institutions, articles, keywords and the citation burst of keywords, researchers exploring the comorbidity between periodontitis and NDs can not only identify potential collaborators and information sources but also gain insights into recent hot topics and emerging mechanisms. Moreover, the emerging research trends reinforce the correlation between periodontitis and NDs, thereby providing clinical practitioners with valuable insights for accurate diagnosis and comprehensive treatment plans. This expanded perspective allows clinicians to recognize the interconnectedness of these seemingly distinct diseases within a unified framework.

Conflict of interest

None disclosed.