CEREBROSPINAL FLUID EVALUATION AS A DIAGNOSIS AND PROGNOSIS TOOL: A BIBLIOMETRIC ANALYSIS OF THE 100 MOST CITED ARTICLES

: Introduction: Cerebrospinal fluid (CSF) analysis is critical in the diagnosis, prognosis, and treatment of a wide range of diseases, including multiple sclerosis, encephalitis, meningitis, brain tumors, Creutzfeldt-Jakob disease, Alzheimer's disease, and other neurodegenerative conditions. Objective: Bibliometric analysis of the 100 most cited articles to obtain deeper insights into the status of research in this sector, in order to provide support for evidence-based medicine (EBM). Methodology: The main collection of the Web of Science was used to collect relevant studies on the topic, and the VOSviewer software was employed to build bibliometric networks. The examination did not include materials from editorials, books, patents, or research with unspecified designs. The articles chosen are in the time range from 1991 to 2020. Results: It was noted that most of the articles were human observational studies focusing on the diagnosis of neurodegenerative diseases, specifically Alzheimer's, which were published in neurology and/or Alzheimer's-related journals, mainly in the United States of America. We discovered forward-looking research hotspots and trends in this domain, which can serve as an important guide to neurological research, generating subsidies for medical decision-making. Conclusion: The number of primary articles on the subject points to the need for further


INTRODUCTION
The cerebrospinal fluid (CSF) is a clear, colorless liquid that fills the ventricles of the brain and the subarachnoid space (CZARNIAK et al., 2023;TUMANI;HUSS;BACHHUBER, 2017;WICHMANN;DAMKIER;PEDERSEN, 2022).It is mostly constituted of water, but it also contains protein, glucose, ions, vitamins, and neurotransmitters.It is created by the choroid plexus of the ventricular system, the interstitial space of the brain, and the subarachnoid space via passive ultrafiltration of fluid through capillaries and active ion transport by choroid plexus endothelial cells (MACAULAY;KEEP;ZEUTHEN, 2022).This production takes place mostly in the lateral ventricles, but it can also be observed in the third and fourth ventricles (CZARNIAK et al., 2023;MACAULAY;KEEP;ZEUTHEN, 2022;TUMANI;HUSS;BACHHUBER, 2017;WICHMANN;DAMKIER;PEDERSEN, 2022).CSF enters the brain and spinal cord's subarachnoid space via the Magendi's foramen and two lateral Luschka's foramina.Furthermore, CSF is absorbed mostly through the arachnoid granulations into the dural venous sinuses, from where it drains into the circulation (CZARNIAK et al., 2023;MACAULAY;KEEP;ZEUTHEN, 2022;TUMANI;HUSS;BACHHUBER, 2017).Convective and pulsatile flow causes this movement in the central nervous system (CNS) (WICHMANN; DAMKIER; PEDERSEN, 2022).
In addition, this fluid serves a variety of essential tasks.It protects the brain from shocks and injuries caused by contact with the skull, reduces brain weight, transmits vital substances for CNS function, and eliminates waste products and hazardous substances from it.It also aids in the maintenance of CNS homeostasis by regulating electrolyte concentrations.It transports both neurotransmitters and hormones which enables the administration of specific drugs directly to the CNS (CZARNIAK et al., 2023;TUMANI;HUSS;BACHHUBER, 2017;WICHMANN;DAMKIER;PEDERSEN, 2022).
Moreover, the cerebrospinal fluid (CSF) assumes critical importance in diagnosing and effectively treating a range of central nervous system (CNS) disorders, including multiple sclerosis, encephalitis, meningitis, brain tumors, Creutzfeldt-Jakob disease, Alzheimer's disease, and other neurodegenerative conditions.CSF can be collected through various methods, such as lumbar puncture, suboccipital puncture, or direct extraction from the lateral ventricles using external ventricular drainage (CZARNIAK et al., 2023;WICHMANN;DAMKIER;PEDERSEN, 2022).
Furthermore, the number of citations serves as a bibliometric parameter indirectly reflecting the impact, quality, and reputation of an article, journal, or author (BALDIOTTI et al., 2021).Employing bibliometric analysis allows for the identification of highly cited papers, facilitating the characterization of scientific output within the relevant field of interest (KAROBARI et al., 2021).While there are published bibliometric assessments that tangentially address the use of cerebrospinal fluid as a diagnostic and prognostic tool (CAI et al., 2022;GUO et al., 2022;LEI et al., 2023;MONJAS-CÁNOVAS et al., 2021;RAMOS-RINCON et al., 2022;SAMANCI;SAMANCI;SAHIN, 2019;WU et al., 2023;ZHANG et al., 2016), direct exploration of its specific application remains lacking.
New approaches using CSF proteins as biomarkers for neurological diseases have been on the spotlight in the past few years, becoming an important field of study and revealing the need of reviews that integrate the knowledge so far in the area.This research will contribute to demonstrate what are the hotspots in CSF studies and if there are any clinical benefits of submitting patients to lumbar puncture.Thus, the objective of this study is to employ bibliometric parameters for identifying and characterizing the scientific literature concerning the use of CSF as a diagnostic and prognostic tool.By examining the 100 most cited articles on this subject, a comprehensive understanding of the current research landscape can be achieved.

METHODS
The Web of Science (WoS) core collection (WoS-CC) database was utilized to gather studies on the diagnosis of diseases through laboratory analysis of CSF on July 12, 2023, using the following search strategy: TS=("cerebrospinal fluid" OR "cerebrospinal liquor" OR "spinal fluid" OR "spinal liquor" OR "CSF" OR "brain fluid" OR "brain liquor") AND TS=("diagnosis" OR "disease diagnosis" OR "disease detection" OR "disease identification") AND TS=("cerebrospinal fluid analysis" OR "cerebrospinal fluid examination" OR "cerebrospinal fluid testing" OR "cerebrospinal fluid biomarkers" OR "cerebrospinal fluid markers" OR "cerebrospinal fluid proteins" OR "cerebrospinal fluid proteomics" OR "cerebrospinal fluid metabolomics" OR "cerebrospinal fluid neurochemicals" OR "cerebrospinal fluid neuroimaging").
Among the search of results related to CSF, the 100 most cited articles were based on citation numbers, abstracts, and complete texts by two independent researchers.Any disagreement was forwarded to a third researcher that was able to reach a primary consensus.Only articles related to the diagnosis by CSF analysis were included.Materials from editorials, books, patents, and articles with unspecified study designs were excluded.
VOSviewer software (www.vosviewer.com) was employed to create coauthorship bibliometric networks and keyword roles.The software assigns nodes to clusters, where each cluster represents a set of closely related nodes.These clusters were represented by different colors.More important terms were depicted as larger nodes and strongly related terms were positioned close to each other.The lines connecting the nodes indicated cooperative relationships, with thicker lines representing stronger links between the specific two terms (SENGUPTA et al., 2020;VAN ECK;WALTMAN, 2010).

General Data
Using the designated search strategy, a total of 2181 publications from the Web of Science main collection were identified in connection with cerebrospinal fluid (CSF) as a clinical marker for disease prognosis, as depicted in Fig. 1.These publications were then fully organized in descending order based on their citation frequency.The 100 most cited articles are listed in Table 1 in descending order according to the total number of citations.The 100 most cited articles were described within a period referring to the years 1991 to 2020.The article "Neurosyphilis and humanimmunodeficiency-virus type-1".JAMA Neurology. 1990, July (BERGER, 1991): is the oldest article, with 65 citations.Likewise, the article "Integrated proteomics reveals brainbased cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease".Sciences Advanced. 2020, October (HIGGINBOTHAM et al., 2020): was the most recent article with the highest number of citations (n=77).
Table 1 The 100 most cited articles on the use of CSF as a diagnostic and/or prognostic tool.

Annual Scientific Production and Citations
All included studies were published between 1991 and 2020.An average annual growth, as of 2009, of 4.9% per year was noticeable.This growth has increased significantly in the last 10 years, with 2019 being the year with the greatest impact regarding the average citation per article, with an average value of 214.67 citations per article, followed by the year 1995, with a value of 214.5 citations per article.The most productive year was 2016 (n=14 articles), followed by 2014 (n=12 articles) and 2011 (n=9 articles).Annual publication output growth is shown in Fig. 2. In addition, the 10 most cited publications are shown in Table 2, along with the annual citation rate (ACR).

Distribution of Authors
The authors of the 100 publications were analyzed and resulted in 5 main clusters.
As for publications, the most prolific authors are Blennow, K (n=20 articles), followed

Distribution of Journals and Countries
The distribution of all 100 publications covered 22 countries/regions.The top 10 countries are shown in Table 3.The United States of America ranked first with a total publication of 27 articles, followed by Sweden with 15 articles, Germany with 10 articles, and the Netherlands with 10 articles.Likewise, the ranking of the most cited countries was not so different, with the USA with 2974 citations, followed by Sweden with 2041 citations, the Netherlands with 1155 citations, and Germany with 720 citations.The collaboration network is represented in Fig. 5.   4.

Distribution of Keywords
All 602 keywords were generated using VOSviewer.We selected only the keywords that occurred in at least 2 articles, identifying a total of 104.The most frequent keywords were represented by occurrence networks as shown in Fig. 6.The most frequent term used was CSF biomarkers (n=67), followed by Alzheimer's Disease (n=42), Mild Cognitive Impairment (n=42), Tau-protein (n=40), and Beta-amyloid (n=31).

DISCUSSION
In this study, a bibliometric analysis was conducted to quantify and visualize trends in publications and research focal points in the field of cerebrospinal fluid (CSF) analysis as a diagnostic tool for disease detection.The research revealed a substantial increase in studies related to CSF analysis, with the United States of America being the prominent driving force due to its high academic standing, reflected by a considerable number of publications and citations attributed to this country.However, it was observed that only one developing country, India, was among the top 10 prolific countries in Table 2 over the last 30 years.This highlights the need for increased collaboration between developed and developing nations to promote advancements in this field.
Another noteworthy aspect pertains to the analysis of cited references.Notably, terms like "CSF biomarkers," "Alzheimer's Disease," "Mild Cognitive Impairment," "Tau-protein," and "beta-amyloid" emerged as key hotspots in the research on CSF

CONCLUSIONS
This bibliometric study provides a comprehensive analysis of global research trends in cerebrospinal fluid (CSF) analysis over a 30-year period and demonstrates that this approach is an important tool for diagnosis and prognosis of neurological patients, mostly for those with neurodegenerative diseases.The identification of potential collaborators, institutions, hotspots, and future research trends contributes valuable insights for guiding future investigations in the clinical diagnostic and prognostic utility of CSF analysis.Moreover, the findings underscore the importance of conducting further research to gain a deeper understanding of significant CSF mechanisms relevant to other neurodegenerative diseases, thereby enhancing diagnostic efficacy.
Furthermore, this research achieves great results and provides background and theoretical support for scientists investigating new approaches to understand neurological diseases.Also, new diagnosis tools and prognosis markers are clinically important to the patients and their physicians.The study limitations were related to the possibility that recent relevant articles in the field do not present a significant number of citations, leaving them out of this research.

Figure. 1
Figure. 1 Flowchart illustrating the process of selection and sorting of articles found in WoS.

Figure. 2
Figure. 2 Distribution of the number of articles produced every two years from 1991 to 2019.

Figure. 3
Figure. 3 Representation of the clusters with the highest number of citations.Authors with the highest number of publications are represented by heat islands that demonstrate citation density.Authors with high citation density are closer, suggesting that publications occur in collaboration between them.

Figure. 4
Figure. 4 Co-authorship network demonstrating bibliographic coupling among the 818 authors of the 100 most cited articles.All authors form 59 clusters.The cluster size demonstrates the frequency of publications.The color scale represents the time interval of the publications.The authors with the highest publication number are superimposed on the authors with the lowest publication number.

Figure. 5
Figure. 5 Co-occurrence network of countries with the highest number of articles on the subject.The cluster size demonstrates the higher frequency of publication of studies.The thickness of the line between the nodes represents the strength of the link between the countries being demonstrated by thicker lines.

Figure. 6 .
Figure. 6. Co-occurrence network of keywords visualized in VOSviewer.The node size represents the frequency of the author keyword with larger nodes indicating greater frequency.The color of the node represents the possibility of co-occurrence of author keywords among the 100 most cited articles with nodes of the same color demonstrating that there is co-occurrence between author keywords in the same article.The thickness of the line between the nodes represents the strength of the link between the author's keywords with strong link strengths being demonstrated by thicker lines.
diagnostics.These biomarkers in cerebrospinal fluid hold prognostic significance for disease monitoring, differential diagnosis, and survival analysis, primarily in neurodegenerative disorders such as Alzheimer's, Parkinson's, and multiple sclerosis(JOHNSON et al., 2020;LO SASSO et al., 2019;PARNETTI et al., 2019).Additionally, other references discussed clinical prognosis and diagnosis of infectious pathologies like meningitis, neurosyphilis, and neurosarcoidosis, as well as dementia-related conditions like frontotemporal degeneration and dementia with Lewy bodies.This emphasizes the valuable contribution of laboratory analysis of biomarkers in CSF for diagnosing and proposing certain nervous system diseases(BAICHURINA et al., 2021).CSF analysis offers a major advantage in identifying specific biomarkers associated with various neurodegenerative pathologies, as evidenced in the articles.For instance, abnormal levels of tau protein and beta-amyloid are commonly found in the CSF of Alzheimer's patients, while α-synuclein serves as a key biomarker for diagnosing Parkinson's disease.The presence of β-amyloid in the CSF is also an important indicator of Alzheimer's (JEROMIN; BOWSER, 2017).Moreover, CSF analysis plays a crucial role in detecting CNS infections and inflammation.The presence of inflammatory cells such as lymphocytes, neutrophils, and macrophages, along with elevated levels of inflammatory proteins, signifies an active immune response, aiding in the differential diagnosis of diseases like meningitis and encephalitis and enabling prompt and appropriate treatment (JULIÁN-JIMÉNEZ; MORALES-CASADO, 2019).In suspected multiple sclerosis cases, the presence of oligoclonal bands of immunoglobulin G in the CSF confirms immune activation in the central nervous system, supporting the diagnosis(LO SASSO et al., 2019).Furthermore, Batista, Barbosa, and Dias (2022) conducted a literature review on the pathophysiology, etiology, and diagnosis of bacterial meningitis.The emphasis was primarily on diagnostic accuracy when using cerebrospinal fluid (CSF) and the continuous evolution of this tool.This enables the achievement of extremely high sensitivity, even in differentiating the etiological agent of the infection.In the case of bacterial meningitis, this will be of paramount importance since the correct choice of antimicrobial therapy will depend on this result (BATISTA; BARBOSA; DIAS, 2022).The most frequently used keywords among the 100 articles underscored a significant focus on diseases like Alzheimer's, Parkinson's, and mild cognitive impairment.This highlights the necessity for further research in cerebrospinal fluid biomarkers to aid in the diagnosis of these diseases and complements other modalities for monitoring clinical prognosis.It is crucial to acknowledge an important limitation of CSF analysis, as it may not be definitive for diagnosing several diseases.Interpretation of results must be combined with clinical information, imaging data, and other laboratory tests to achieve accurate diagnosis.Furthermore, reference values for CSF analysis may vary among different laboratories, posing challenges in result comparison.Hence, it is essential to consider these variabilities and perform serial analyses when required.

Table 2
Top 10 most cited articles classified according to their characteristics.

Table 3
Top 10 countries in descending order in scientific production.

Table 4
Top 10 most relevant journals with their respective Impact Factor.