Unveiling the Landscape of Toll-Like Receptors in Cognitive Dysfunction: A Bibliometric Analysis

doi:10.21203/rs.3.rs-4612490/v1

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Unveiling the Landscape of Toll-Like Receptors in Cognitive Dysfunction: A Bibliometric Analysis

https://doi.org/10.21203/rs.3.rs-4612490/v1

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OBJECTIVES

Toll-like receptors (TLRs) are transmembrane proteins primarily involved in the immune response, mediating the pathophysiological process of cognitive impairment through pathways. Despite an abundance of literature elucidating the role of TLRs in cognitive dysfunction, bibliometric analyses of this topic are notably scarce.

METHODS

We conducted a bibliometric analysis of publications spanning from 2002 to 2023, retrieved from the widely utilized Web of Science Core Collection, employing tools such as R language, CiteSpace software, and the online bibliometric platform (https://bibliometric.com/) for a comprehensive visual analysis. Data analysis was performed using GraphPad Prism and IBM SPSS.

RESULTS

Our findings revealed a total of 502 articles published over the past 11 years. Notably, China contributed significantly, accounting for 39.84% (n = 200) of the publications, underscoring its prominence in this field. The Journal of Brain Behavior and Immunity emerged as the leading journal in terms of article contributions, with 40 publications (7.07%). Author influence, measured by the H-index, highlighted Baluchnejadmojarad, Tourandokht, and Roghani, Mehrdad, as the two most influential authors, each with an H-index of 9. The co-occurrence analysis of keywords revealed that terms such as "activation", "toll-like receptors", and "inflammation" were consistently prevalent in the literature.

CONCLUSION

This visualized bibliometric analysis demonstrated the progress in research related to TLRs in cognitive dysfunction, with a gradual increase in literature volume over the past 11 years. Researchers can derive valuable insights into research trends, frontiers, and influential authors from our study, aiding them in shaping their future research endeavors in this field.

bibliometric analysis

CiteSpace

TLRs

cognitive

Cognitive dysfunction, also referred to as cognitive impairment, can be delineated as a state of functioning that falls below the anticipated normative levels or entails a decline in the capacity to perform cognitive tasks across various domains^1,2, is a prevalent manifestation in various pathological or disease states. Cognitive dysfunction can be influenced by various factors; nevertheless, the underlying mechanism responsible for cognitive dysfunction remains insufficiently understood. ^3,4. previous studies showed that neuroinflammation plays a significant role in cognitive dysfunction's initiation and development⁵, the aberrant activation of Toll-like receptors (TLRs) in microglia elicits neuroinflammatory reactions, thereby precipitating a deterioration in cognitive capabilities⁶. As such, TLRs have emerged as crucial mechanisms for understanding cognitive dysfunction and investigating potential therapeutic targets.

TLRs are a specific group of pattern recognition receptors (PRRs) that are recognized for their essential roles in two key functions⁷. Firstly, TLRs act as initiators of both innate and adaptive host defense mechanisms against infections by recognizing molecular patterns associated with diverse microbes. Secondly, TLRs play a significant role in the generation of inflammatory cytokines and the development of autoinflammatory responses⁸.The current understanding is that the activation of TLRs plays a crucial role in initiating the inflammatory response and triggering the production of proinflammatory cytokines^9,10. Specifically, Toll-like receptor 4 has been identified as a mediator of cognitive decline induced by sevoflurane in mice¹¹. Additionally, in stressful conditions, the up-regulation of TLR7 is prompted by an increase in let-7b, which initiates downstream inflammatory signaling and significantly contributes to perioperative neurocognitive disorders¹². TLRs have gained significant importance in cognitive research due to their essential involvement in the regulation of cognitive dysfunction, thereby presenting promising opportunities for comprehending and addressing cognitive disorders.

In recent years, bibliometric analysis has gained significant momentum for its capacity to offer quantitative insights into collaborations among organizations, publications, and scientific research trends¹³. To our knowledge, no bibliometric analysis focusing on TLRs in cognitive dysfunction has hitherto been published. To address this gap, we systematically searched related publications within the Web of Science Core Collection (WoSCC) and subsequently conducted a visualized bibliometric study. We sought to uncover intricate relationships within this literature and provide valuable information that can guide and inform researchers in future studies on TLRs and cognitive dysfunction.

2.1 Data Collection

The data for this study were collected from WOSCC, encompassing the Social Sciences Citation Index (SSCI), the Science Citation Index Expanded (SCI-Expanded), and the Emerging Sources Citation Index (ESCI). As of October 3, 2023, a total of 684 publications were retrieved using the search strategy: TI = (Cognitive or Cognitive dysfunction or Cognitive impairment) and (Toll-like receptor or Toll-like receptors or TLRs or TLR) (Fig. 1).

2.2 Inclusion Criteria

Articles on TLRs in the context of cognitive dysfunction.

Articles published between January 1, 2002 and October 3, 2023.

Literature indexes from WOSCC, SSCI, SCI-Expanded, and ESCI.

Journal articles written in English.

2.3 Exclusion Criteria

Articles not officially published.

Review article, early access, proceeding paper, meeting abstract, book chapters, retracted publication, correction, editorial material, Letter.

Duplicated publications.

Topic-unrelated articles.

2.4 Quality Assessment

This bibliometric analysis was performed only on English articles that met the inclusion criteria but not the exclusion criteria.

2.5 Analysis tools

The organization, analysis, and visualization of data were carried out using three different software programs. CiteSpace (6.2 R4) was employed for analyzing authors, countries/regions, references, keywords, and authors/co-cited authors, as well as journals. Additionally, the annual publication trends and the treemap chart of the 50 most frequently used keywords and the most frequently cited references were analyzed using an online bibliometric platform (https://bibliometric.com/). For other statistical and cartographic analyses, GraphPad Prism (version 9.0) and IBM SPSS (version 25.0) were utilized.

3.1 Analysis of publication outputs

As shown in Fig. 2, research in cognitive science has demonstrated a steady annual increase from 2007 to 2023. Over this period, there has been a consistent growth in the number of research papers addressing the interplay between TLRs and cognitive processes. Starting from 2011, there has been an average annual increase of over 10 articles, representing an Annual Growth Rate of 22.18%, with a peak of 68 articles in the year 2023. While the rise in publications was relatively gradual from 2007 to 2014, a continuous upward trend has been observed since 2017. The surge in TLRs research focusing on cognitive mechanisms can be attributed to advancements in fundamental research methods and sustained scientific enthusiasm. By October 4, 2023, a cumulative total of 45 articles have been published, and there is an expectation of additional contributions in the future. The escalating number of yearly publications underscores the dynamic and promising role that TLRs play in advancing cognitive research.

3.2 Analysis of countries and institutions

Our analysis encompassed contributions from 47 countries/regions, resulting in a total of 502 papers that met the inclusion criteria. As detailed in Table 1, China emerged as the most prolific country/region in terms of scientific work publication, contributing 200 papers, followed by the United States (n = 132), South Korea (n = 26), and Canada (n = 21). Furthermore, the United States took the lead in the number of citations, amassing a total of 7,821. The top three countries in terms of centrality were the United States (0.68), Germany (0.35), and China (0.21), while several other countries, including South Korea, Iran, and Italy, exhibited productivity with a centrality of less than 0.1. As illustrated in Fig. 3, each country/region displayed a varying degree of cooperation. The corporation map of countries indicates a strong integration of collaborative efforts between China and the USA, followed by England, Canada, and Germany.

Table 1

Top 10 most productive countries/regions.
Countries/Regions	Publications	Citations	Average citations per item	Centrality
PEOPLES R CHINA	200	4,867	24.34	0.21
USA	132	7,821	59.25	0.68
SOUTH KOREA	26	746	28.69	0.00
CANADA	21	1,303	62.05	0.13
ENGLAND	18	1,230	68.33	0.18
IRAN	18	487	27.06	0.00
ITALY	18	857	47.61	0.04
EGYPT	17	209	12.29	0.09
AUSTRALIA	16	962	60.13	0.11
SPAIN	16	1,012	63.25	0.03

As shown in Table 2, several institutions emerged as notable contributors to the publication landscape on TLRs in cognitive science. In terms of publications, the University of California System secured the top position with 19 publications, followed closely by the Egyptian Knowledge Bank with 17 publications and Cairo University with 11 publications. The top 10 most productive institutions prominently featured representatives from both the United States and Egypt, reflecting a strong presence and contribution from these regions in advancing research on TLRs in cognitive science.

Table 2

Top 10 most productive institutions.
Rank	Institution	Country	publications	Centrality
1	University of California System	USA	19	0.12
2	Egyptian Knowledge Bank (EKB)	Egypt	17	0.00
3	Cairo University	Egypt	11	0.00
4	National Institutes of Health (NIH) - USA	USA	10	0.11
5	University System of Ohio	USA	9	0.04
6	Iran University of Medical Sciences	Iran	9	0.00
7	Shahed University	Iran	8	0.00
8	Nanjing Medical University	China	8	0.00
9	Laval University	Canada	8	0.00
10	Gyeongsang National University	South Korea	8	0.00

3.3Analysis of journals and co-cited journals

The 502 papers on TLRs in cognitive science were distributed across 238 different journals. The top ten productive journals in publishing articles on this topic are presented in Table 3, contributing 25.30% (127 publications) to the overall output. According to the results, BRAIN BEHAVIOR AND IMMUNITY published the highest number of articles (40, 7.97%), followed by JOURNAL OF NEUROINFLAMMATION and MOLECULAR NEUROBIOLOGY (22, 4.38%), MOLECULAR NEUROBIOLOGY (12, 2.39%), and BEHAVIOURAL BRAIN RESEARCH (9, 1.79%). BRAIN BEHAVIOR AND IMMUNITY received the most citations, followed by JOURNAL OF NEUROINFLAMMATION, with both journals surpassing others in terms of citations. Notably, these two journals also boasted the highest H-index and impact factor among all the journals (H-index: 22, 17; 2023 IF: 6.633, 5.793).

Table 3

The top 10 most productive journals
Journals	Publications	Citations	Average citations per tem	H_ index	2023 IF
BRAIN BEHAVIOR AND IMMUNITY	40	2,006	50.15	22	6.633
JOURNAL OF NEUROINFLAMMATION	22	1,998	90.82	17	5.793
MOLECULAR NEUROBIOLOGY	12	309	25.75	9	4.5
BEHAVIOURAL BRAIN RESEARCH	9	156	17.33	8	2.977
PLOS ONE	8	362	45.25	6	2.74
SCIENTIFIC REPORTS	8	579	72.38	7	3.998
FRONTIERS IN PHARMACOLOGY	7	75	10.71	5	4.225
INTERNATIONAL IMMUNOPHARMACOLOGY	7	96	13.71	5	3.943
JOURNAL OF ALZHEIMERS DISEASE	7	235	33.57	7	3.909
JOURNAL OF NEUROSCIENCE	7	562	80.29	6	5.765

As shown in Table 4, the top 10 co-cited journals with the highest counts/centrality in research on TLRs in cognitive science are presented. Four co-cited journals (PLOS ONE, Proc Natl Acad Sci U S A, JOURNAL OF NEUROINFLAMMATION, JOURNAL OF NEUROSCIENCE) had over 250 co-citations. According to centrality, PLOS ONE, Proc Natl Acad Sci U S A, JOURNAL OF NEUROINFLAMMATION, JOURNAL OF NEUROSCIENCE, and BRAIN BEHAVIOR AND IMMUNITY ranked as the top 5 sources. Notably, the top 10 co-cited journals with the most citations and centrality were all based in the United States.

Table 4

The top 10 co-cited journals
Rank	Counts	Co-cited Journal	2023 IF^a	contry	Rank	Centrality	Co-cited Journal	2023 IF	contry
1	299	PLOS ONE	2.74	UNITED STATES	1	0.11	PLOS ONE	2.74	UNITED STATES
2	281	Proc Natl Acad Sci U S A	9.41	UNITED STATES	2	0.1	Proc Natl Acad Sci U S A	9.41	UNITED STATES
3	275	JOURNAL OF NEUROINFLAMMATION	5.793	ENGLAND	3	0.07	JOURNAL OF NEUROINFLAMMATION	5.793	ENGLAND
4	273	JOURNAL OF NEUROSCIENCE	5.765	UNITED STATES	4	0.06	JOURNAL OF NEUROSCIENCE	5.765	UNITED STATES
5	245	BRAIN BEHAVIOR AND IMMUNITY	6.633	UNITED STATES	5	0.05	BRAIN BEHAVIOR AND IMMUNITY	6.633	UNITED STATES
6	211	JOURNAL OF IMMUNOLOGY	2.217	UNITED STATES	6	0.05	JOURNAL OF IMMUNOLOGY	2.217	UNITED STATES
7	201	JOURNAL OF BIOLOGICAL CHEMISTRY	4.238	UNITED STATES	7	0.05	JOURNAL OF BIOLOGICAL CHEMISTRY	4.238	UNITED STATES
8	191	NEUROSCIENCE	3.05	ENGLAND	8	0.04	NEUROSCIENCE	3.05	ENGLAND
9	191	NATURE	42.778	ENGLAND	9	0.04	NATURE	42.778	ENGLAND
10	191	JOURNAL OF NEUROCHEMISTRY	4.7	ENGLAND	10	0.04	JOURNAL OF NEUROCHEMISTRY	4.7	ENGLAND
^aIF in category according to Journal Citation Reports (2021). IF, impact factor.

3.4 Analysis of authors and co-cited authors

The 502 papers on TLRs in cognitive science were authored by a total of 3,248 contributors. Table 5 highlights the top ten authors based on their publication records. The most prolific authors included BALUCHNEJADMOJARAD T and ROGHANI M (n = 9 publications each), followed by AFSHIN-MAJD S and GUERRI C (n = 7 publications), and PASCUAL M and KIASALARI Z (n = 6 publications). GUERRI C garnered the highest number of citations (575), trailed by PASCUAL M with 351 citations. PASCUAL M also boasted the highest average citations among the top authors. BALUCHNEJADMOJARAD T and ROGHANI M, both with an H-index of 9, emerged as the five most influential authors. A visual representation of the author network is provided in Fig. 4a.

Table 5

Top ten most productive authors
Author	Publications	Citations	Average citations per tem	H_ index
BALUCHNEJADMOJARAD T	9	384	42.67	9
ROGHANI M	9	384	42.67	9
AFSHIN-MAJD S	7	290	41.43	7
GUERRI C	7	575	82.14	7
PASCUAL M	6	536	89.33	6
KIASALARI Z	6	247	41.17	6
ZHANG J	5	171	34.20	5
ZHANG X	4	193	48.25	7
LYNCH MA	4	352	88.00	4
HEO HJ	4	32	8.00	3

Table 6 presents the ten co-cited authors based on their publications, and Fig. 4b illustrates the interconnectedness of co-cited authors in the network. In terms of co-cited counts, OKUN E (73), HENEKA MT (46), and KAWAI T (44) secured the top three positions. Additionally, for co-cited authors with centrality, TAHARA K (0.25) and OKUN E (0.12) exhibited higher centrality values compared to other researchers.

Table 6

Top ten co-cited authors
Rank	Author	Counts	Centrality
1	OKUN E	73	0.12
2	HENEKA MT	46	0.05
3	KAWAI T	44	0.08
4	WALTER S	41	0.1
5	LEHNARDT S	41	0.1
6	WANG Y	38	0.04
7	TAHARA K	34	0.25
8	LIU Y	31	0.07
9	ROLLS A	31	0.02
10	RICHARD KL	30	0.05

3.5 Analysis of the 10 most-cited papers

The academic impact of a research study can be assessed by the number of citations it receives in the literature. Table 7 presents the top 10 most-cited papers on TLRs in cognitive science, along with the average citations for these top 10 cited papers. Out of the 502 publications, the citation counts for the top 10 most-referenced papers ranged from 222 to 679, collectively constituting 20.93% of all citations. The most-cited paper, titled "Inflammation in Alzheimer's disease-a brief review of the basic science and clinical literature" by WYSS-CORAY T, was published in Cold Spring Harb Perspect Med in 2012. Among the top 10 papers based on citation counts, only two were published within the past five years. Notably, "Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice" by ZHAO JY, published in Scientific Reports, and "Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-κB Signaling" by MUHAMMAD T, published in Nutrients, represent the most recent and highly cited literature in the field. Furthermore, these papers exhibited the highest average number of citations per year, underscoring their significant contribution to advancing our understanding of cognitive mechanisms.

Table 7

The top 10 papers in the number of citations
Title	Journal	Year	Citations	2023 IF
Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature.	Cold Spring Harb Perspect Med	2012	679	6.00
Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline.	Proc Natl Acad Sci U S A	2010	518	9.41
Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia.	J Neuroinflammation	2008	479	5.79
Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines.	Brain Behav Immun	2009	412	6.63
Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice.	Sci Rep	2019	370	4.00
Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.	Biol Psychiatry	2015	359	12.10
Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study.	J Neuroinflammation	2012	336	5.79
Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of Alzheimer's disease.	J Neurosci	2008	250	5.67
Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-κB Signaling.	Nutrients	2019	235	4.55
Inflammation in epilepsy: clinical observations.	Epilepsia	2011	222	6.04
Average per year
Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice.	Sci Rep	2019	74.00	4.00
Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature.	Cold Spring Harb Perspect Med	2012	56.58	6.00
Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-κB Signaling.	Nutrients	2019	47.00	4.55
Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.	Biol Psychiatry	2015	39.89	12.10
Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/ TLR4/ NF-κB pathways in BV2 cells.	Mol Immunol	2019	38.60	3.64
Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline.	Proc Natl Acad Sci U S A	2010	37.00	9.41
Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice.	Acta Pharm Sin B	2020	35.75	7.10
Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia.	J Neuroinflammation	2008	29.94	5.79
Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease.	Acta Neuropathol	2019	29.20	14.25
SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties.	Brain Behav Immun	2022	28.50	6.63

3.6 Analysis of keywords

A total of 152 keywords were extracted, with 60 terms appearing more than 10 times and 9 terms emerging more than 50 times in the field of TLRs in cognitive dysfunction. Figure 5a displays the Word Cloud Map composed of these keywords, emphasizing the aspect of highest frequency and centrality. The top 10 most frequent keywords in this specialized research field are presented in Table 8 and Fig. 5b, with "activation" (112 papers, 7%), "toll-like receptors" (99 papers, 6%), and "inflammation" (96 papers, 5%) identified as the three most important keywords, based on their frequency of mention in publications. Keywords with citation bursts signify the development of specific knowledge areas. Figure 5c showcases the top 25 keywords about TLRs in cognitive dysfunction with the strongest citation bursts since 2004. The temporal boundaries of the research frontier and the duration of the research frontier are indicated by the length of the red bars. Furthermore, Fig. 5d illustrates the intensity of mutation, with five clusters of keywords representing distinct areas of research. The magnitude of the outbreak reflects the intensity of change and development in the research landscape related to TLRs in cognitive dysfunction.

Table 8

The top 10 keywords with the highest centrality and counts
Rank	Keyword	Counts	Inital year	Rank	Keyword	Centrality	Inital year
1	activation	112	2007	1	inflammation	0.13	2010
2	toll like receptors	99	2010	2	mouse model	0.12	2009
3	inflammation	96	2010	3	activation	0.11	2007
4	expression	84	2009	4	expression	0.09	2009
5	alzheimers disease	81	2007	5	oxidative stress	0.09	2007
6	brain	74	2009	6	brain	0.08	2009
7	mouse model	54	2009	7	prefrontal cortex	0.08	2009
8	oxidative stress	52	2007	8	disease	0.07	2009
9	cognitive impairment	50	2010	9	hmgb1	0.07	2015
10	microglia	49	2013	10	Toll-like receptors	0.06	2010

3.7 Analysis of Reference

Table 9 provides valuable insights into citation patterns and influential works in the field of TLRs in cognitive dysfunction. A study by Okun E¹⁴ garnered significant attention, holding the highest number of citations at 12 and a centrality of 0.12, indicating its significance and impact. Figure 6a illustrates the cooperative relationships and references of TLRs in cognitive processes over time. The increasing number and size of nodes signify growing influence and collaboration among researchers. Colors represent referenced years, while intricate connection lines denote the complexity of relationships between references. The graph, arranged chronologically from left to right, demonstrates an increasing number and size of nodes, as well as a growing quantity and complexity of connection lines. In Fig. 6b, references are clustered based on focal points, representing specific topics or themes. Core references are marked by their centrality and frequency. TLRs in cognitive research involves several sub-clusters, including cognitive deficits, normal brain aging, symptoms of inflammation-induced sickness, basic science, act, new drug target, and more. Figure 6c highlights references with high burst values, indicating emerging trends in TLRs in cognitive science from 2013 to 2023. Okun E¹⁴ stood out with a burst value of 5.29, revealing TLR3 as a suppressor of hippocampal cellular plasticity and memory retention. Another significant burst value (4.97) is associated with Reed-Geaghan EG ¹⁵, suggesting that innate immune receptors TLR4 and TLR2, components of the microglial fibril β-amyloid (fAβ) receptor complex, promote microglial activation. The analysis of research references on TLRs in cognitive science provides valuable insights into emerging trends and research directions. Researchers can use these references to stay informed about recent developments and contribute to the advancement of cognitive research. Coupling clusters, including the main clusters of "toll-like receptors", "oxidative stress", and "rats," as well as the latest research frontiers encompassing topics such as "tlr4", "stroke", "microglia", "health", "astrocytes", "risk", "damage", and "receptors", are visualized in Fig. 6d. Additional coupling clusters involving "mobility group box-1, temporal-lobe epilepsy, antiepileptic drugs ", "central-nervous-system, microglial activation, blood-brain-barrier", "prefrontal cortex, toll-like receptor-3, brain-damage", "activation, inflammation, expression", and "lobectomy, surgery, cognition, models", are also displayed.

Table 9

The top 10 references in the field of TLRs in cognitive
Rank	Counts	Centrality	Author	year	Source
1	12	0.11	Okun E	2010	PNAS
2	11	0.04	Heneka MT	2015	Lancet. Neurology
3	10	0.07	Reed-Geaghan EG	2015	Journal of neuroscience
4	10	0	Gambuzza M	2014	CNS & neurological disorders drug targets
5	9	0.07	Maroso M	2010	Nature medicine
6	9	0.01	Hanke M	2011	Clinical science
7	8	0	Michaud JP	2013	PNAS
8	8	0.12	Tahara K	2006	Brain: a journal of neurology
9	8	0	Trotta T	2014	Journal of neuroimmunology
10	8	0.08	Richard K	2008	Journal of neuroscience

The role of TLRs in cognitive-related diseases remains elusive, despite abundant fundamental scientific research. This bibliometric analysis, covering the literature from 2002 to 2023, employed quantitative and visualization techniques to illuminate various dimensions of current research on TLRs in cognitive dysfunction. The analysis revealed a consistent rise in annual publications, emphasizing the growing significance of TLRs in cognitive dysfunction. Prestigious journals such as BRAIN BEHAVIOR AND IMMUNITY and JOURNAL OF NEUROINFLAMMATION have played a pivotal role in highlighting interdisciplinary attention to Toll-like receptors in cognitive dysfunction. The collaborative network highlighted the crucial contributions of China and the United States, with influential figures like Professor OKUN E instrumental in understanding TLR mechanisms in cognitive dysfunction. ^16,17. Citation bursts, particularly those of ROGHANI M and BALUCHNEJADMOJARAD T, indicated their potential influence ^18,19. This comprehensive analysis provides a broader perspective on Toll-like receptor research in cognitive dysfunction, facilitating the development of future endeavors, collaborations, and navigating this evolving landscape with stakeholders in the field.

In the exploration of TLRs in cognitive mechanisms, several pivotal research findings have assumed a crucial guiding role, leading to their recognition as highly cited articles. The analysis of the top 10 papers, based on their citation frequency, sheds light on significant contributions to the field. One notable contribution is Tony Wyss Coray et al.'s paper, published in the Cold Spring Harb Perspect Med journal. This work posits that immune and inflammatory processes in genes, cells, and molecules are intricately linked to cognitive impairment in Alzheimer's disease. The authors highlight anti-inflammatory approaches as a key direction that holds promise for improving cognitive dysfunction in Alzheimer's disease ²⁰. Another noteworthy study, conducted by Jiayi Zhao et al., is titled "Neuroimaging induced by lipopolysaccharide causes cognitive impairment in mice", and it boasts the highest annual average citation. Zhao et al.'s findings support the notion that lipopolysaccharide (LPS) triggers microglial activation through the NF-kB signaling pathway, leading to cognitive impairment and neuroinflammation²¹. The cumulative impact of these highly cited articles, both in terms of total citations and annual average citations, suggests a strong association between TLRs-mediated neuroinflammation and the regulation of cognitive dysfunction ^22,23.

The analysis of TLRs research-related keywords has revealed key hotspots that reflect the evolving landscape of the field. Through keyword sorting and clustering, the top three frequently occurring terms were identified as "activation", "toll-like receptors", and "inflammation". Toll-like receptors play a critical role in regulating innate immunity and the inflammatory response. In the context of Alzheimer's disease, the presence of nucleic acid-containing amyloid fibrils induces interferon and activates TLRs, leading to neuroinflammation and synapse loss ²⁴. The exploration of how TLR activation mediates cognitive dysfunction is an ongoing area of investigation. For instance, the activation of Toll-like receptor 2 through high mobility group box-1 has been linked to postoperative neuroinflammation and cognitive dysfunction in mice, showcasing the continuous exploration of these mechanisms²⁵. The development of the field is discernible through keyword citation bursts. Notably, between 2008 and 2013, a substantial body of literature emerged employing transgenic mice to investigate potential mechanisms of TLRs in cognitive dysfunction. María Pascual et al. made a significant contribution during this period by demonstrating, in genetically modified mice, that alcohol-induced inflammation is mediated by TLR4 function²⁶. This work further indicated that alcohol-induced behavioral and cognitive impairments result from epigenetic modifications mediated by TLR4 ²². Since 2019, there has been a shift in the keyword landscape, with terms such as "shock", "microglia", and "damage" emerging as prominent themes. This shift suggests that research on TLRs in cognition has entered a new direction, signaling ongoing exploration and evolution in the understanding of the complex interplay between TLRs and cognitive processes²⁷.

Analyzing references is a valuable approach to discerning important trends and impactful works in TLRs research on cognitive dysfunction. One notable reference is Okun E's study ¹⁴ which stands out for its high citation rate. This suggests that the study is not only of high quality but also deemed crucial within the field, signifying its importance as a key research work. Additionally, renowned investigations by Maroso M²⁸ and Hanke M¹⁷ have been published in top-tier journals. These studies have significantly contributed to enriching scientists' understanding of the role of Toll-like receptors in cognitive dysfunction. The publication of such works in reputable journals indicates their impact on the field and underscores their importance in shaping the current knowledge landscape surrounding TLRs and cognitive dysfunction.

Conclusion

Overall, this comprehensive visualized bibliometric analysis offers valuable insights into emerging areas, trends, and potential directions for TLRs in cognitive research. Our study reveals that TLRs play a pivotal role in cognitive dysfunction, spanning from fundamental mechanisms to potential clinical applications. This research promises to usher in a new era of advancements in medicine, with the goal of benefiting patients and advancing the field of medical science. Empowered by these insights, researchers are poised to make significant contributions to the ever-evolving landscape of TLRs in cognitive dysfunction, further shaping the trajectory of this critical area of study.

Acknowlegments

The team expresses gratitude to Professor Zou Jiang of the Anesthesiology Department at Sichuan Cancer Hospital for providing guidance in the study of bibliometrics.

Conflict of interest

The authors declare that they have no competing interests.

Funding

This work was supported by Youth Science Foundation of Natural Science Foundation of Sichuan (Grant No. 2022NSFSC1346); and Medical Research Project in Sichuan Province (Grant No. S21052); and Bethune Charitable Foundation (NO. ezmr2023-031).

Author Contribution

AZ and QL were involved in the conception and study design. AZ and H W were involved in the writing and revision of the manuscript. QL was responsible for the data analysis. AZ was in charge of concept design, article proofreading and project guidance. All authors were responsible for critical revision of the manuscript and reviewed the manuscript.

Data Availability

It is included in the article that the authors' original contributions are described in more detail. Further inquiries may be directed to the corresponding authors.

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No competing interests reported.

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Unveiling the Landscape of Toll-Like Receptors in Cognitive Dysfunction: A Bibliometric Analysis

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Abstract

OBJECTIVES

METHODS

RESULTS

CONCLUSION

Figures

1. Introduction

2. Materials and methods

2.1 Data Collection

2.2 Inclusion Criteria

2.3 Exclusion Criteria

2.4 Quality Assessment

2.5 Analysis tools

3. Results

3.1 Analysis of publication outputs

3.2 Analysis of countries and institutions

3.3Analysis of journals and co-cited journals

3.4 Analysis of authors and co-cited authors

3.5 Analysis of the 10 most-cited papers

3.6 Analysis of keywords

3.7 Analysis of Reference

4. Discussion

Declarations

Acknowlegments

Conflict of interest

Funding

Author Contribution

Data Availability

References

Additional Declarations

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