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ASSOCIATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS WITH RISK OF ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

 

S.S. Zakariaee1,2, N. Naderi3, E. Azizi4

 

1. Department of Medical Physics, Faculty of Paramedical Sciences, Ilam University of Medical Sciences, Ilam, Iran; 2. Non-Communicable Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran; 3. Department of Midwifery, Faculty of Nursing and Midwifery, Ilam University of Medical Sciences, Ilam, Iran;
4. Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran.

Corresponding Author: Seyed Salman Zakariaee, Department of Medical Physics, Faculty of Paramedical Sciences, Ilam University of Medical Sciences, Ilam, Iran. Email address: salman_zakariaee@yahoo.com, Tel: +988432227122, Cell: +989188783551

J Prev Alz Dis 2024;
Published online January 15, 2024, http://dx.doi.org/10.14283/jpad.2024.18

 


Abstract

BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative illness that leads to impairment of cognitive functions and memory loss. Even though there is a plethora of research reporting the abnormal regulation of VEGF expression in AD pathogenesis, whether the CSF and serum VEGF are increased in AD is an open question yet. In this study, the association of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease was investigated using systematic review and meta-analysis.
METHODS: A systematic literature search was carried out using online specialized biomedical databases of Web of Science, Pubmed, Scopus, Embase, and Google Scholar until Feb 2023 without restriction to the beginning time. The meta-analysis was performed using the random-effects model and only case-control publications describing VEGF concentrations in Alzheimer’s patients were considered for calculating the pooled effect size.
RESULTS: In the systematic literature search, 6 and 13 studies met the inclusion criteria to evaluate CSF and serum VEGF concentrations of Alzheimer’s patients, respectively. This meta-analysis retrieved a total number of 2380 Alzheimer’s patients and 5368 healthy controls. Under the random-effects model in the meta-analysis, the pooled SMD for CSF and serum VEGF concentrations of Alzheimer’s patients were -0.13 (95%CI,-0.42–0.16) and 0.23 (95%CI,-0.27–0.73), respectively. Results of meta-regression analysis showed that the quality scores of papers and female sex ratios of participants did not affect the associations of VEGF concentrations with the risk of Alzheimer’s disease. However, the age average of patients significantly affects the associations of CSF VEGF concentrations with the risk of Alzheimer’s disease (P=0.051). There was a statistically significant subgroup effect for the disease severity of Alzheimer’s patients which modifies the associations of serum VEGF concentrations with the risk of Alzheimer’s disease (P<0.01) and subgroup analysis shows that study location modifies the associations of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease (P<0.01).
CONCLUSION: The results show that the serum VEGF concentrations increased for Alzheimer’s patients in accordance with the increased expression of VEGF and the VEGF levels of Alzheimer’s patients decreased by increasing their disease severities. Therefore, in addition to detecting AD in the earliest stages of the disease, serum VEGF could be a promising biomarker to follow up on the disease and evaluate the clinical course of the disease.

Key words: Vascular endothelial growth factor, VEGF, Alzheimer, dementia.


 

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative illness that leads to impairment of cognitive functions and memory loss (1, 2). This chronic neurodegenerative disease affects one in eight elderly people over 60 years old and includes 50-60% of dementia patients (2-4). With the aging of the population and growing prevalence of AD, the accurate and reliable diagnosis of Alzheimer’s patients in the earliest stages of the disease has become a public health priority (3, 5-7). Currently, clinical diagnosis of AD is largely based on the symptoms of the patients, measuring the concentrations of phosphorylated tau (pTau) and amyloid-b (Ab) factors in cerebrospinal fluid (CSF), and measures of amyloid burden and brain atrophy using imaging approaches. These diagnostic criteria, even in most experienced medical centers, had a limited degree of accuracy (approximately 70%) (2). Therefore, identification of new biomarkers that are easily accessible in fluids like blood could provide a window to the early identification of AD especially when their distinguishing from the effects of aging is challenging.
In the etiology of AD, cerebral neovascularization occurs in response to impaired cerebral perfusion and inflammation (8). Regional increase of capillary density, development of vascular loop and glomeruloid vascular structure, and expression of vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF -α), and transforming growth factor β (TGF-β) confirmed this hypothesis (8, 9). For AD, vascular endothelial cell is one of the main factors in the progressive destruction of cortical neurons and angiogenesis activate large populations of endothelial cells in brain hypoxia and inflammation (8, 9). Therefore, chronic cerebral hypoperfusion which generally results in the upregulation of angiogenesis (10) played a significant initial role than previously understood.
Complex interplay of humoral and cellular factors controls angiogenesis and in response to hypoxia observed in AD, several studies reported dysregulation of humoral factors related to angiogenesis (such as VEGF) and the interaction of inflammation and angiogenesis(10). VEGF are the most potent mitogens acting on endothelial cells (8, 11-13). This hypoxia-inducible angioneurin regulates vascular, blood-brain barrier, and neural functions (14). For Alzheimer patients, the increased reactivity in VEGF had been reported in response to the regulatory mechanisms compensating for reduced cerebral perfusion and insufficient brain tissue vascularity (15). VEGF is an angiogenic cytokine involved in AD pathophysiology and there is increasing evidence of VEGF alterations in CSF and serum of Alzheimer’s patients (1, 14).
Even though there is a plethora of research reporting the abnormal regulation of VEGF expression in AD pathogenesis, a dedicated systematic review and meta-analysis study has not yet been performed and actually, whether the CSF and serum VEGF are increased in AD is an open question yet. In this study, the alterations of CSF and serum VEGF concentrations of Alzheimer’s patients compared to healthy subjects were investigated using systematic review and meta-analysis.

 

Methods and Materials

Protocol of the systematic review and meta-analysis

In this study, to conduct a systematic review and meta-analysis of VEGF concentrations relating to the risk of Alzheimer’s disease, the PRISMA 2009 Checklist was applied (16).

Information sources and search strategies

A systematic literature search was independently carried out by three authors (SS. Z., N. N., and E. A.) using online specialized biomedical databases of Web of Science, Pubmed, Scopus, Embase, and Google Scholar until Feb 2023 without restriction to the beginning time. We used the following MeSH and non-MeSH terms:
“vascular endothelial growth factor», VEGF, “Alzheimer’s Disease”, “Dementia, Senile”, “Senile Dementia”, “Dementia, Alzheimer Type”, “Alzheimer Type Dementia”, “Alzheimer-Type Dementia (ATD)”, “Alzheimer Type Dementia (ATD)”, “Dementia, Alzheimer-Type (ATD)”, “Alzheimer Type Senile Dementia”, “Primary Senile Degenerative Dementia”, “Dementia, Primary Senile Degenerative”, “Alzheimer Sclerosis”, “Sclerosis, Alzheimer”, “Alzheimer Syndrome”, “Alzheimer Dementia”, “Alzheimer Dementias”, “Dementia, Alzheimer”, “Dementias, Alzheimer”, “Senile Dementia, Alzheimer Type”, “Acute Confusional Senile Dementia”, “Senile Dementia, Acute Confusional”, “Dementia, Presenile”, “Presenile Dementia”, “Alzheimer Disease, Late Onset”, “Late Onset Alzheimer Disease”, “Alzheimer’s Disease, Focal Onset”, “Focal Onset Alzheimer’s Disease”, “Familial Alzheimer Disease (FAD)”, “Alzheimer Disease, Familial (FAD)”, “Alzheimer Diseases, Familial (FAD)”, “Familial Alzheimer Diseases (FAD)”, “Alzheimer Disease, Early Onset”, “Early Onset Alzheimer Disease”, “Presenile Alzheimer Dementia”, “Alzheimer Disease”, CSF, “cerebrospinal fluid”, hormone, plasma, serum, “blood samples”, circulatory, level* , “case-control study”. Boolean operators (NOT, AND, OR) were used in succession.
The publication references were also screened to identify any additional relevant studies. The review processes were limited to case-control studies, and case reports, editorials, commentaries, and opinions were not included in the study.

Eligibility criteria and study selection

Only publications describing VEGF concentrations in Alzheimer’s and healthy subjects were considered for calculating the pooled effect size (SMD, standardized mean difference). No limitation was applied to the Alzheimer subtype, disease severity, race, sex, and age of study participants reported by included studies. If the studies enrolled individuals other than Alzheimer’s patients, they were excluded. The publications whose full texts are not available or the number of cases and healthy controls were not reported were excluded from the meta-analysis processes. Three authors separately selected the included studies and any disagreement has been resolved through discussion.

Data collection process

The first author of the included publications, date and location of publication, VEGF concentrations of Alzheimer’s and healthy subjects, the total number of cases and healthy controls, disease severity of the Alzheimer patients, and other related information were extracted from the included studies.

Summary measures and synthesis of results

For data analyses, Stata version 14.0 (Stata Corporation, College Station, TX, USA) was used.
Between-study heterogeneity was evaluated using the χ2-based Q test and I2 index statistics. The estimated SMDs of VEGF concentrations for included studies and also overall effect size were determined with the 95% confidence interval (CI). An SMD of zero means that case and control groups have the same mean concentrations of VEGF. The data extracted from included studies are listed in Table 1. These data were used for the calculation of the pooled SMD.

Table 1. The demographic information extracted from the included studies reporting CSF and serum VEGF concentrations of Alzheimer’s and healthy subjects

£ Median, IQR

 

Assessment of quality of studies

For assessing the quality and risk of bias of the included studies, the Newcastle–Ottawa Scale (NOS) was used. This tool evaluates the quality of the case–control studies based on selection (0–4 points), comparability (0–2 points), and exposure (0–4 points) definitions. The studies would categorized as good, fair, and poor qualities if they scored as ≥ 7 points, 5–6 points, and < 5 points, respectively. The quality of the studies was independently assessed by two investigators (N. N. and E. A.) and any discrepancy was resolved through discussion.

Risk of bias across studies

Visual inspection of the funnel plot was used for the interpretation of any publication bias among the included studies. In this plot, the X and Y axes represent the standard error and standardized mean differences (SMDs), respectively.

 

Results

Study selection

In the included studies, the VEGF concentrations were measured in CSF and serum samples of the subjects. Therefore, we investigated the association of VEGF concentrations in CSF and serum samples with the risk of Alzheimer’s disease, separately. The publication selection processes for CSF and serum VEGF concentrations of Alzheimer’s patients were summarized in Figure 1.

Figure 1. Search strategy for systematic review. Nineteen studies fulfilled the inclusion/ exclusion criteria

 

The initial search for CSF and serum VEGF concentrations of Alzheimer’s patients retrieved a total of 525 potentially eligible publications. These records were screened for detection of duplicate studies and after duplicate removal, 339 papers remained. Of the remained studies, 259 articles were excluded due to their irrelevance to the aim of the study and reporting the insufficient data regarding SMD and 95% CI calculations. Publications with a case-control study design that reported VEGF concentrations in Alzheimer’s patients (without considering Alzheimer’s subtypes and disease severity) were included in the meta-analysis processes.
Finally, nineteen case-control studies were selected to evaluate the association of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease. The final included studies evaluating CSF and serum VEGF concentrations of Alzheimer’s patients are detailed in Table 1.

Study characteristics

For each publication, epidemiological data including the age average, female sex ratio, number of participants in cases and healthy subjects, Alzheimer’s subtype, and severity of disease were extracted. The epidemiological and disease characteristics data are presented in Tables 1 and 2. Finally, this meta-analysis retrieved a total number of 2380 Alzheimer’s patients and 5368 healthy controls until Feb 2023.
The NOS tool for case–control studies were used to evaluate the quality of studies and the results are shown in Table 1. The scores for the studies reporting CSF VEGF concentrations of Alzheimer’s patients were as follows: 9/10 score [3 studies (30%)]; 8/10 score [5 studies (50%)]; and 7/10 score [2 studies (20%)]. The scores for the studies reporting serum VEGF concentrations of Alzheimer’s patients were as follows: 10/10 score [4 studies (19.05%)]; 9/10 score [1 study (4.76%)]; 8/10 score [9 studies (42.86%)]; and 7/10 score [7 studies (33.33%)]. The quality of the included studies was not the source of heterogeneity among the studies because all studies were categorized as good quality (scores of ≥ 7).

Table 2. CSF and serum VEGF concentrations of Alzheimer’s and healthy subjects reported by the included studies

 

Risk of bias within studies

The heterogeneity between studies could be assessed using the p-value obtained from the χ2 test. If there is a low p-value, the heterogeneity between studies is significant. The p-values obtained from the χ2 test of heterogeneity were < 0.001 for studies reporting CSF and serum VEGF concentrations of Alzheimer’s patients. Moreover, the I2 test for studies reporting CSF and serum VEGF concentrations of Alzheimer’s patients was calculated as 79.7% and 98.0%, respectively. Therefore, the random-effects model of the meta-analysis was applied to evaluate the associations of both VEGF concentrations with the risk of Alzheimer’s disease.

Synthesis of results

The forest plots for the included studies reporting CSF and serum VEGF concentrations of Alzheimer’s patients are presented in Figure 2. In these plots, the SMDs and their 95% CIs for included studies and the overall effect size (SMD) with a 95%CI are demonstrated. Under the random-effects model in the meta-analysis, the pooled SMD for CSF and serum VEGF concentrations of Alzheimer’s patients were -0.13 (95% CI, -0.42 – 0.16) and 0.23 (95% CI, -0.27 – 0.73), respectively. The pooled SMD estimates were significant (P<0.001).

Figure 2A. Forest plots for included studies. These graphs show the weights and SMDs (with 95%CI) of the studies in determining the pooled effect size. At the bottom of the graphs, the pooled effect sizes (the pooled SMDs and their 95% CIs) are shown

a) In this plot, pooled data evaluating the serum VEGF concentrations of Alzheimer’s patients compared to healthy subjects have been demonstrated under the random-effects model. The pooled estimate for serum VEGF concentrations of Alzheimer’s patients was calculated as 0.19 (95% CI 0.29–0.66)

Figure 2B. Forest plots for included studies. These graphs show the weights and SMDs (with 95%CI) of the studies in determining the pooled effect size. At the bottom of the graphs, the pooled effect sizes (the pooled SMDs and their 95% CIs) are shown

b) In this plot, pooled data evaluating the CSF VEGF concentrations of Alzheimer’s patients compared to healthy subjects have been demonstrated under the random-effects model. The pooled estimate for CSF VEGF concentrations of Alzheimer’s patients was calculated as -0.13 (95% CI -0.42–0.16)

 

Risk of bias across studies

In Figure 3, the funnel plots seemed symmetrical in shape demonstrating the absence of publication bias in the finally included articles reporting CSF and serum VEGF concentrations of Alzheimer’s patients (P = 0.14 and 0.746, respectively).

Figure 3A. Funnel plots for included studies. The generated funnel plots were visually inspected to evaluate the existence of any publication bias among studie

a) The funnel plot seemed symmetrical in shape (p = 0.686) which demonstrates the absence of publication bias in the results of included studies evaluating the serum VEGF concentrations of Alzheimer’s patients

Figure 3B. Funnel plots for included studies. The generated funnel plots were visually inspected to evaluate the existence of any publication bias among studies

b) The funnel plot seemed symmetrical in shape (p = 0.14) which demonstrates the absence of publication bias in the results of included studies evaluating the CSF VEGF concentrations of Alzheimer’s patients. In these plots, the Y and X axes represent the SMDs of VEGF concentrations for Alzheimer’s patients and the standard error of these SMDs, respectively.

 

Meta-regression analysis was conducted on the quality scores of papers, female sex ratios of participants, and age averages of cases to explore the possible sources of between-study heterogeneities. Results showed that the quality scores of papers, female sex ratios of participants, and age averages of cases did not affect the associations of serum VEGF concentrations with the risk of Alzheimer’s disease (P = 0.578, 0.142, and 0.307, respectively). The quality scores of papers and the female sex ratios of participants did not also affect the associations of CSF VEGF concentrations with the risk of Alzheimer’s disease (P = 0.691 and 0.532, respectively). But, the age average of cases significantly affects the associations of CSF VEGF concentrations with the risk of Alzheimer’s disease (P = 0.051). The effect of the age average of Alzheimer’s patients on their CSF VEGF concentrations is depicted in Figure 4. To evaluate other possible sources of heterogeneities, study location, and disease severity were investigated in subgroup analysis.

Figure 4. Meta-regression graph to determine the effect of age average of Alzheimer’s patients on their CSF VEGF concentrations

As it is evident, the age average of Alzheimer’s patients significantly affected their CSF VEGF concentrations (p = 0.053). So that CSF VEGF concentrations of Alzheimer’s patients decrease with their age average increasing. The X and Y axes represent the age average of Alzheimer’s patients (year) and SMDs of CSF VEGF concentrations in Alzheimer’s patients, respectively.

 

The test for subgroup differences indicated that there is no statistically significant subgroup effect for disease severity in CSF VEGF concentrations (P = 0.52) but there was a statistically significant subgroup effect for serum VEGF concentrations (P<0.01). Forest plots for included studies evaluating the CSF and serum VEGF concentrations of Alzheimer’s patients according to the location of studies are presented in Figure 5. These results indicate that disease severities of Alzheimer’s patients only modify the associations of serum VEGF concentrations with the risk of Alzheimer’s disease. For both CSF and serum VEGF concentrations quantified for Alzheimer’s patients, there were statistically significant subgroup effects for study location (P<0.01) suggesting that study location modifies the associations of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease. In Figure 6, the results of subgroup analysis for included studies evaluating the CSF and serum VEGF concentrations of Alzheimer’s patients according to the severity of the disease are presented.

Figure 5A. Forest plots for included studies evaluating the CSF and serum VEGF concentrations of Alzheimer’s patients according to the location of studies. These graphs show the weights and SMDs of the studies in determining the pooled effect size for each study location. At the end of the sections, the overall effect size (SMD with its 95%CI) related to each location of the study is indicated

a) In this presentation, pooled data evaluating the serum VEGF concentrations of Alzheimer’s patients have been demonstrated for each country under the random-effects model

Figure 5B. Forest plots for included studies evaluating the CSF and serum VEGF concentrations of Alzheimer’s patients according to the location of studies. These graphs show the weights and SMDs of the studies in determining the pooled effect size for each study location. At the end of the sections, the overall effect size (SMD with its 95%CI) related to each location of the study is indicated

b) In this presentation, pooled data evaluating the CSF VEGF concentrations of Alzheimer’s patients have been demonstrated for each country under the random effects model. In subgroup analysis, when there is one reported study in a subgroup, I2, H2, and p values cannot be calculated. Therefore, these values are presented as NC

Figure 6A. Forest plots for included studies evaluating the CSF and serum VEGF concentrations of Alzheimer’s patients according to the severity of the disease. These graphs show the weight and SMDs (with 95%CI) of the studies in determining the pooled effect size for different severities of disease. At the end of the sections, the overall effect size (SMD with its 95%CI) related to each severity of disease is indicated

a) In this presentation, pooled data evaluating serum VEGF concentrations of Alzheimer’s patients have been demonstrated for each severity of disease under the random-effects model

Figure 6B. Forest plots for included studies evaluating the CSF and serum VEGF concentrations of Alzheimer’s patients according to the severity of the disease. These graphs show the weight and SMDs (with 95%CI) of the studies in determining the pooled effect size for different severities of disease. At the end of the sections, the overall effect size (SMD with its 95%CI) related to each severity of disease is indicated

b) In this presentation, pooled data evaluating CSF VEGF concentrations of Alzheimer’s patients have been demonstrated for each severity of disease under the random effects model. In subgroup analysis, when there is one reported study in a subgroup, I2, H2, and p values cannot be calculated. Therefore, these values are presented as NC

 

Discussion

Angiogenesis as a complex process involving numerous humoral and cellular factors plays a critical role in to development and maintenance of the neurovascular unit (10). Multiple stimuli (including hypoxia, inflammation, etc.) could upregulate or down-regulate angiogenesis and aberrant angiogenesis has been well-documented for neurodegenerative diseases (10). Angiogenesis is involved in neurogenesis, a process critical to preserving hippocampal function and thus episodic memory processes. VEGF is a homodimeric glycoprotein that, in addition to vasculogenesis and angiogenesis, is also involved in aberrant angiogenesis (10). This hypoxia-induced signaling protein significantly affected the regulation of physiological and pathological angiogenesis(3). Although VEGF is probably the most widely studied angiogenesis factor in the field of AD (10), its role remains uncertain. Investigations on CSF and serum VEGF concentrations in Alzheimer patients yielded controversial results showing higher, similar, and even lower concentrations for Alzheimer patients compared to the control subjects (1, 3, 4, 7, 8, 14, 15, 18, 23). To address these inconsistencies and determine how CSF and serum VEGF concentrations change in AD, the CSF and serum VEGF concentrations of Alzheimer’s patients were investigated to explore whether the CSF and serum VEGF concentrations of Alzheimer’s patients would be higher than those of control subjects.
Although there are original and review articles describing the CSF and serum VEGF concentrations in Alzheimer’s patients, the true directions of the alterations in the CSF and serum VEGF concentrations for AD have been a matter of debate in recent original and review articles. No meta-analysis study has to date been carried out on this subject. To the best of our knowledge, this report is the first meta-analysis describing the CSF and serum VEGF concentrations of Alzheimer’s patients compared to healthy subjects to provide evidence to determine the efficiencies of CSF and serum VEGF concentrations for early diagnosis and comprehensive understanding of the disease.
The primary analysis on a total number of 2380 Alzheimer’s patients found that the final combined SMDs for CSF and serum VEGF concentrations in Alzheimer’s patients compared to the healthy controls were -0.13 (95%CI, -0.42–0.16) and 0.23 (95%CI, -0.27–0.73), respectively. These results show that the alteration of serum VEGF concentrations is in accordance with the increased expression of VEGF. These observations confirm the hypothesis of the occurrence of hypoxia and cerebromicrovascular changes (2, 4, 8). The reason for observing an increase in serum VEGF concentration and VEGF concentration decreasing in CSF samples could be due to the structure and integrity of the blood-brain barrier (BBB), which causes the impenetrability of the blood-brain barrier. BBB does not allow the exchange of substances between blood (serum or plasma) and CSF easily.
In meta-regression analysis, results showed that the female sex ratio and study quality score did not affect the CSF and serum VEGF concentrations of Alzheimer’s patients. This result could be because all studies were categorized as good quality and the upregulated expression of VEGF, which leads to compensatory angiogenesis, is independent of the patient’s gender. The age average of the patients did not affect the serum VEGF concentrations of the patients but significantly affected their CSF VEGF concentrations (P= 0.051). So that SMD of CSF VEGF concentrations in Alzheimer’s patients decrease with their age average increasing.
For both CSF and serum VEGF concentrations of Alzheimer patients, a significant subgroup effect was observed for the study location (P <0.01). It means that the study location significantly modifies CSF and serum VEGF concentrations of Alzheimer’s patients. These differences can be mainly due to the different approaches used in these study locations and their measurement performances. In similar experimental setups with similar materials and subjects, the sensitivity and accuracy of measurements would be different even for two identical devices manufactured by the same company. This issue becomes more complicated with the utilization of diverse measurement kits for different human samples. The CSF and serum VEGF concentrations of Alzheimer’s patients decrease by increasing their disease severity. A significant subgroup effect was observed for the severity of disease in serum VEGF concentrations of Alzheimer’s patients (P <0.01) that confirmed the fact that the disease severity significantly modifies serum VEGF concentrations of Alzheimer’s patients. No significant subgroup effect was observed for disease severity in CSF VEGF concentrations of Alzheimer’s patients (P =0.52). This might be due to the absence of patients with high disease severity in the reported studies.
This study paves the way to provide preliminary evidence that the serum VEGF concentration increased in Alzheimer’s patients and the VEGF concentrations of the patients decreased by increasing their disease severity. Such blood-based biomarkers that could detect AD in the earliest stages of the disease will be of paramount importance for patient management because of the convenience, cost-effectiveness, and non-invasive nature of their sample collection process. VEGF could also offer a new therapeutic target to prevent or delay the onset of AD through modulation of angiogenesis.

 

Conclusion

Although VEGF is probably the most widely studied angiogenesis factor in the field of AD, investigations on CSF and serum VEGF concentrations in Alzheimer patients yielded controversial results showing higher, similar, and even lower concentrations for Alzheimer patients compared to the control subjects. To address these inconsistencies and determine how VEGF concentrations change in AD, the CSF and serum VEGF concentrations of Alzheimer’s patients were investigated to explore whether the CSF and serum VEGF concentrations of Alzheimer’s patients would be higher than those of control subjects.
The results show that the serum VEGF concentrations increased for Alzheimer’s patients in accordance with the increased expression of VEGF. These observations confirm the hypothesis of the occurrence of hypoxia and cerebromicrovascular changes. The reason for observing an increase in serum VEGF concentration and VEGF concentration decreasing in CSF samples could be due to the structure and integrity of the blood-brain barrier (BBB), which causes the impenetrability of the blood-brain barrier. BBB does not allow the exchange of substances between blood (serum or plasma) and CSF easily.
The CSF and serum VEGF concentrations of Alzheimer’s patients decreased by increasing their disease severity. Therefore, in addition to detecting AD in the earliest stages of the disease, serum VEGF could be a promising biomarker to follow up on the disease and evaluate the clinical course of the disease.

 

Acknowledgements: The authors would like to thank the research affair of Ilam University of Medical Sciences.

Funding: This study was funded by Ilam University of Medical Sciences.

Ethics approval and consent to participate: The study was approved by the local Medical Ethical Committee.
Consent for publication: Not applicable.

Availability of data and material: All data generated or analyzed during this study are included in the article.

Competing interests: The authors declare that they have no competing interests.

Authors’ contributions: Seyed Salman Zakariaee: Content planning, Literature Search and Review, Data collection, Manuscript writing and editing, and Meta-Analysis. Negar Naderi: Literature Search and Review, Data collection, and Manuscript editing. Esfandyar Azizi: Project development, Literature Search and Review, Manuscript writing and editing.

 

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