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. 2023 Mar;22(3):311–316.

Relation of Cognitive Impairment with Number of Acute Exacerbations and Serum Level of VEGF among COPD Patients

Mitra Samareh Fekri 1, Ahmad Nagibzadeh Tahami 2, Fateme Arabnejad 3,✉
PMCID: PMC11022191  PMID: 38638387

Abstract

Background:

Chronic obstructive pulmonary disease (COPD) is a main cause of morbidity and mortality in the world. Its complications are numerous and one of their most common extra-pulmonary ones is cognitive impairment which is directly related to its mortality and morbidity. A decrease in cerebral perfusion in these patients had been seen in previous studies considering the role of VEGF on angiogenesis and its role in the pathogenesis of COPD. This study was done to evaluate the relation of cognitive impairment with serum VEGF and the number of COPD exacerbations.

Materials and Methods:

In the present study, 87 patients whom the pulmonologist confirmed their COPD disease based on spirometry testing were enrolled. The blood sample was received for serum VEGF level measurement and the Mini-Mental State Examination (MMSE) questionnaire was completed to assess the cognitive function. The number of exacerbations was also recorded. The blood sample was received from 87 other age and sex-matched persons without a history of pulmonary disease, CVA, or MI. Their VEGF level was also measured. The data was analyzed by SPSS version 20 software.

Results:

In the COPD group, 42 (48.28%) had no cognitive impairment, 39 (44.83%) had mild, and 6(6.89%) had moderate cognitive impairment. In this group, there was a significant relation between the score of the MMSE questionnaire and the number of COPD exacerbations during the past year. However, there was no significant relation between VEGF and cognitive impairment.

Conclusion:

According to the results of the present study, there was no significant relation between cognitive impairment and VEGF level. There was a significant relation between cognitive impairment and the number of COPD exacerbations. Also, there was a significant difference between the serum level of VEGF among COPD patients and the control group.

Keywords: COPD, Cognitive impairment, Serum VEGF, MMSE, Lung diseases

INTRODUCTION

COPD or chronic obstructive pulmonary disease is defined as irreversible restriction of air flow in the lung and decrease of FEV1/FVC ratio. It has three clinical subgroups: chronic bronchitis, emphysema, and small airway disease. The average age of incidence is 50 years old and more than 14% of the people aged more than 65 are affected (1). COPD has different risk factors including environmental risk factors (cigarette smoking, air pollution, occupational exposure to dust and smoke) and genetic risk factors (2).

Emphysema is the enlargement of the lung because of the expansion of alveoli and atrophy of the septum. Vascular endothelial growth factor (VEGF) is a main modulator of physiologic and pathologic angiogenesis. In emphysema, the endothelial cells of the lung will experience apoptosis because of diminished VEGF and consequently, the sensitivity of the alveolar walls will increase for oxidant stress and proteinases (3). The serological level and also the number of VEGF receptors decrease in emphysema (4).

There is a hypothesis that the imbalance between VEGF and endostatin (VEGF antagonist) causes emphysema in COPD patients (5) and the increased serum VEGF causes remodeling of the airway in chronic bronchitis COPD patients (6). The recent studies have shown that VEGF is not only effective on angiogenesis in the CNS but also has direct neuroprotective effects on the neurons and has a neurotropic effect. It also increases the permeability of the blood-brain barrier to glucose and activates the anti-oxidants (7, 8). Many studies have shown increased VEGF levels among Alzheimer patients in comparison with normal people. The patients who had more rapid cognitive decline had more VEGF levels (9, 10).

VEGF has an important role in many diseases such as vasculitis and hematologic malignancies.

Beside its role as an essential regulator of physiologic and pathologic angiogenesis, VEGF triggers growth, survival, and migration of leukemia and multiple myeloma cells; plays a pivotal role in hematopoiesis; inhibits maturation of dendritic cells; and increases osteoclastic bone-resorbing activity as well as osteoclast chemotaxis. Dysregulation of VEGF expression and signaling pathways therefore plays an important role in the pathogenesis and clinical features of hematologic malignancies, in particular, multiple myeloma. (11) Increased plasma VEGF could be a useful marker for the diagnosis of vasculitis neuropathy and for monitoring a therapeutic effect (12). VEGF levels are raised in Wegner patients compared to normal controls and may be a marker of disease activity (13).

COPD is one of the main causes of mortality and morbidity in the world. Also, the most common presentation of COPD is diminished air flow, but it is related to many extrapulmonary manifestations which relate to morbidity, lower quality of life, and even mortality (14). It is linked with many extrapulmonary complications such as osteoporosis, anemia, and cardiovascular disease. Thus, it is considered a multi-system disease.

Cognitive impairment is one of the most common extrapulmonary manifestations of COPD and is related to mortality and morbidity (15). In a systematic review, it was shown that cognitive function is impaired in COPD patients compared to normal people (16). In the Valipour study, it is shown that the serum VEGF level in stable COPD patients is more than the control group (17).

In fact, by considering the relation of serum VEGF with the pathogenesis of COPD, the number of acute exacerbations of diseases, and the relation of VEGF with cognitive impairment, there is a question that if the VEGF levels could be the cause of more cognitive impairment among COPD patients? And does cognitive impairment correlate with the number of exacerbations in COPD patients?

MATERIALS AND METHODS

This study has the ethical confirmation from the Kerman Medical University Ethics Committee (k/95/178). In the present case-control study, from the patients with a history and presentations of COPD who were visited by a pulmonologist in Afzalipour hospital, Kerman, 87 Patients with stable disease, aged between 40–85 years and without a history of acute exacerbation during the past three months and confirmed COPD (FEV1/FVC < 0.7 that would not increase with two puffs of salbutamol spray and the FEV1 would not increase more than 12% or 200 cc, by the spirometry test (Spirolab III MIR, ITALY)) entered the study. 87 age and sex-matched family members of patients from different parts of the hospital were selected as the control group. Exclusion criteria were illiteracy, cerebrovascular accident, and myocardial infarction. The goals of the study were described and informed consent was received. MMSE questionnaire was completed and O2 saturation was measured by pulse oximeter (Zyklusmed, Germany) for the case and control group. A form for the history of kidney disease, diabetes mellitus, hypertension, hyperlipidemia, and number of COPD exacerbations during the past year was filled. Then, 2cc of venous blood was received, centrifuged, and stoked at −80 degrees centigrade to measure the serum VEGF level. The MMSE questionnaire is a 30-score questionnaire that is used for cognitive impairment and consists of 5 parts: attention and calculation (5 scores), recall (13 scores), language (9scores), orientation (10 scores), and recording (3 scores). The score equal or more than 25 is the normal range. 20–24 score shows mild cognitive impairment, below 9 shows severe, and 10–19 shows moderate cognitive impairment. Validity and accuracy of the Persian translation of this questionnaire is measured by Seyedian et al. with Cronbach’s alpha of 81%. Its accordance with Wechsler adult intelligence scale was 85% with 90% sensitivity and 93.5% specificity (18).

After sample collection, the serum samples were evaluated with quantitative human VEGF kit (Bioassay Technology, China) and data was analyzed with SPSS20 software.

RESULTS

In the case group, 8 (9%) were female and 79 (91%) were male while in the control group 10 (11%) were female and 77 (89%) were male. The average age of COPD patients was 60.47 ± 9.8 years (between 43–83 years) and 60.41±7.8 years (between 45–80 years) in the control group. In the case group 42 (48.28%) had no cognitive impairment, 39 (44.83%) mild, and 6 (6.89%) had moderate cognitive impairment. In COPD group, there was a significant relation between the score of MMSE questionnaire and number of COPD exacerbations during the past year (correlation coefficient: −0.617) and the number of coexisting systemic diseases (correlation coefficient: −0.477, p-value<0.0001) (Figure 1).

Figure 1.

Figure 1.

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The relation of number of COPD exacerbation with MMSE score in COPD patients

Serum level of VEGF in COPD patients was 489.22±33.37 (range 117.1–980.8). There was no significant relation between serum VEGF level and the score of MMSE questionnaire (Pearson correlation: −0.109, p-value: 0.499).

Serum level of VEGF was 253±155.62 in the control group (range: 157.34–315.01). There was a significant difference between the serum VEGF level of the case and control group (p-value<0.0001).

In the control group, 75 (86.2%) patients had no cognitive impairment, 9 (10.34%) had mild, and 3 (3.46%) had moderate cognitive impairments. There was a significant difference between the MMSE scores of the cases and controls (p-value < 0.0001; mean difference: 1.12). The MMSE score was 23.63 ± 2.8 in the control group and 22.51 ± 2.4 in the case group.

There was also an inverse relationship between the number of exacerbations and MMSE score (p < 0.0001).

DISCUSSION

To our best knowledge, there was no study for evaluating the relation of VEGF and cognitive impairment in COPD patients. In the present study, 51.73% of COPD patients had a degree of cognitive impairment which has been reported variously in different studies. The prevalence of cognitive impairment among COPD patients varies considering the sample selection, the considered age, the tests which were used to assess cognitive impairment such as MMSE, P 300, severity of COPD disease, and even the method of approving the COPD disease (a questionnaire for clinical presentations of COPD or spirometry). The results vary from no association between COPD and cognitive impairment in some studies (19) to 77% prevalence of cognitive impairment among COPD patients (20).

The present study did not show a relation between serum VEGF level and MMSE score as an indicator of cognitive impairment. Although, there was no relation between these two, but it can be due to specific VEGF level changes in different forms of COPD. As mentioned in the introduction, the serum VEGF level decreases in emphysema and increases in chronic bronchitis form of COPD (4,6,7). Considering this point that the present study didn’t distinguish between two types of COPD because of the need for using advanced methods such as CT scan that was not feasible for us, so the relation between VEGF and cognitive impairment might be covered for this reason.

Similar to some studies (17, 20, 21, 22), in the present study, the level of serum VEGF was significantly higher in COPD patients in comparison with normal people. However, other study (23) did not find any difference between the VEGF levels of these two groups. The discrepancies could be because of a lack of differentiating chronic bronchitis from emphysema form (by noting their difference in VEGF levels).

By noting the adverse relation between serum VEGF and PaO2, we can conclude that in acute exacerbation, hypoxia induces neo-angiogenesis and more perfusion and oxygenation using VEGF (22, 24). Although, another study says that the sputum VEGF level increases during the exacerbation, but there was no change in the serum level of VEGF (25).

Interestingly, Lee has reported that deletion of VEGF signal by activating Recombinant Luteinizing Hormone (RLH) caused more viral infections in COPD patients. It might be concluded that in fact, the increase of VEGF level is an immune response of body to the exacerbation (26).

In the study of Kirkil et al. in 2007 on 17 healthy, 30 stable COPD patients, an d 30 COPD patients in exacerbation, it was shown that cognitive impairment was more among both groups of COPD compared to normal people and was more in exacerbations than stable COPD patients. It is mentioned that cognitive impairment and FEV1 and PaO2 will regress to the basal level over time, after healing the exacerbation (27). However, in the study of Dodd et al. in 2013, it was mentioned that cognitive function will decrease in acute exacerbations and is related to the general condition and duration of hospitalization. It is also shown that this decrease in cognitive function had no significant healing in 3 months of follow-up (28). In two other studies, Federman et al. (29) and Ozyemisci-Taskiran et al. (30), it is shown that COPD patients experience cognitive impairment during the exacerbation of COPD.

There was also a significant adverse relation between the score of MMSE questionnaire with number of exacerbations and number of coexisting systemic diseases. For the relation of cognitive impairment with number of exacerbations many studies (24–27) are designed in a way that they have compared a group of stable COPD with a group of exacerbated COPD for cognitive impairment. Indeed, they have assessed their transient increase of cognitive impairment and not the long term effect of number of acute COPD exacerbations on cognitive impairment.

Although, one study had considered a three-month follow-up for the patients and it was mentioned that the induced cognitive impairment had no significant recovery in the three months of follow-up (25). However, in the present study, the patients were in stable situation and the number of COPD exacerbations during the past year was asked from the patient, retrospectively. There was a significant relation between the number of COPD exacerbations and cognitive impairment even in the stable state that could be an indicator of long term effects of each previous acute exacerbation on cognitive status of the patient.

We could assess the relation of VEGF and cognitive impairment much better if we could distinguish the emphysema from chronic bronchitis type. The study could be better if we had a larger sample size.

CONCLUSION

According to the results of the present study, there was no significant relation between cognitive impairment and VEGF level. There was a significant relation between cognitive impairment and number of COPD exacerbations and there was a significant difference between the serum level of VEGF among COPD patients and the control group.

REFERENCES

  • 1.Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370(9589):765–73. [DOI] [PubMed] [Google Scholar]
  • 2.Antonelli-Incalzi R, Corsonello A, Trojano L, Pedone C, Acanfora D, Spada A, et al. Screening of cognitive impairment in chronic obstructive pulmonary disease. Dement Geriatr Cogn Disord 2007;23(4):264–70. [DOI] [PubMed] [Google Scholar]
  • 3.Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 2001;163(3 Pt 1):737–44. [DOI] [PubMed] [Google Scholar]
  • 4.Kanazawa H, Hirata K, Yoshikawa J. Imbalance between vascular endothelial growth factor and endostatin in emphysema. Eur Respir J 2003;22(4):609–12. [DOI] [PubMed] [Google Scholar]
  • 5.Rovina N, Papapetropoulos A, Kollintza A, Michailidou M, Simoes DC, Roussos C, et al. Vascular endothelial growth factor: an angiogenic factor reflecting airway inflammation in healthy smokers and in patients with bronchitis type of chronic obstructive pulmonary disease? Respir Res 2007;8(1):53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Kanazawa H, Asai K, Nomura S. Vascular endothelial growth factor as a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of COPD. Respir Res 2007;8(1):22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 2009;29(6):789–91. [DOI] [PubMed] [Google Scholar]
  • 8.Storkebaum E, Lambrechts D, Carmeliet P. VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 2004;26(9):943–54. [DOI] [PubMed] [Google Scholar]
  • 9.Tang H, Mao X, Xie L, Greenberg DA, Jin K. Expression level of vascular endothelial growth factor in hippocampus is associated with cognitive impairment in patients with Alzheimer’s disease. Neurobiol Aging 2013;34(5):1412–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Hohman TJ, Bell SP, Jefferson AL, Alzheimer’s Disease Neuroimaging Initiative . The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease. JAMA Neurol 2015;72(5):520–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2005;105(4):1383–95. [DOI] [PubMed] [Google Scholar]
  • 12.Sakai K, Komai K, Yanase D, Yamada M. Plasma VEGF as a marker for the diagnosis and treatment of vasculitic neuropathy. J Neurol Neurosurg Psychiatry 2005;76(2):296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Li CG, Reynolds I, Ponting JM, Holt PJ, Hillarby MC, Kumar S. Serum levels of vascular endothelial growth factor (VEGF) are markedly elevated in patients with Wegener’s granulomatosis. Br J Rheumatol 1998;37(12):1303–6. [DOI] [PubMed] [Google Scholar]
  • 14.Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J 2010;35(4):913–22. [DOI] [PubMed] [Google Scholar]
  • 15.Federman AD, Wolf MS, Sheng T, O’Conor R, Martynenko M, Wisnivesky J. Diminished Cognitive Function Among Chronic Obstructive Pulmonary Disease Patients During Periods of Acute Illness Exacerbation. J Gerontol A Biol Sci Med Sci 2016;71(2):279–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Kirdar S, Serter M, Ceylan E, Sener AG, Kavak T, Karadağ F. Adiponectin as a biomarker of systemic inflammatory response in smoker patients with stable and exacerbation phases of chronic obstructive pulmonary disease. Scand J Clin Lab Invest 2009;69(2):219–24. [DOI] [PubMed] [Google Scholar]
  • 17.Arslan S, Yildiz F, Baris SA, BOYACI H, Basyigit I. Systemic Inflammation and Comorbidities in Stable and Exacerbation Periods of Chronic Obstructive Pulmonary Disease. Acta Medica 2015;31:243. [Google Scholar]
  • 18.Seyedian M, Fallah M, Nourouzian M, Nejat S, Delavar A, Ghasemzadeh H, et al. Validity of the Farsi version of mini-mental state examination. Journal of Medical Council of Iran 2008; 25(4):408–14. [Persian] [Google Scholar]
  • 19.Ozge C, Ozge A, Unal O. Cognitive and functional deterioration in patients with severe COPD. Behav Neurol 2006;17(2):121–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Valipour A, Schreder M, Wolzt M, Saliba S, Kapiotis S, Eickhoff P, et al. Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. Clin Sci (Lond) 2008;115(7):225–32. [DOI] [PubMed] [Google Scholar]
  • 21.Kierszniewska-Stepień D, Pietras T, Górski P, Stepien H. Serum vascular endothelial growth factor and its receptor level in patients with chronic obstructive pulmonary disease. Eur Cytokine Netw 2006;17(1):75–9. [PubMed] [Google Scholar]
  • 22.El-Margoushy NE, Mansour AM, El-Nashar NA, Hatem M, Mohamed EH. Vascular Endothelial Growth Factor And Adiponectin As Inflammatory Markers In Acute Exacerbation Of Chronic Obstructive Pulmonary Disease. Journal of International Academic Research for Multidisciplinary 2015; 3(3): 222–31. [Google Scholar]
  • 23.Chu LF. Plasma inflammatory biomarkers in stable COPD patients. HKU Theses Online (HKUTO) 2012.
  • 24.Ortapamuk H, Naldoken S. Brain perfusion abnormalities in chronic obstructive pulmonary disease: comparison with cognitive impairment. Ann Nucl Med 2006;20(2):99–106. [DOI] [PubMed] [Google Scholar]
  • 25.Lázár Z, Bikov A, Gálffy G, Losonczy G, Horváth I. Sputum VEGF level increases with treatment of COPD acute exacerbation. European Respiratory Journal 2012: P3228. [Google Scholar]
  • 26.Lee SH, Lee SH, Kim CH, Yang KS, Lee EJ, Min KH, et al. Increased expression of vascular endothelial growth factor and hypoxia inducible factor-1α in lung tissue of patients with chronic bronchitis. Clin Biochem 2014;47(7–8):552–9. [DOI] [PubMed] [Google Scholar]
  • 27.Kirkil G, Tug T, Ozel E, Bulut S, Tekatas A, Muz MH. The evaluation of cognitive functions with P300 test for chronic obstructive pulmonary disease patients in attack and stable period. Clin Neurol Neurosurg 2007;109(7):553–60. [DOI] [PubMed] [Google Scholar]
  • 28.Dodd JW, Charlton RA, van den Broek MD, Jones PW. Cognitive dysfunction in patients hospitalized with acute exacerbation of COPD. Chest 2013;144(1):119–27. [DOI] [PubMed] [Google Scholar]
  • 29.Federman AD, Wolf MS, Sheng T, O’Conor R, Martynenko M, Wisnivesky J. Diminished Cognitive Function Among Chronic Obstructive Pulmonary Disease Patients During Periods of Acute Illness Exacerbation. J Gerontol A Biol Sci Med Sci 2016;71(2):279–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Ozyemisci-Taskiran O, Bozkurt SO, Kokturk N, Karatas GK. Is there any association between cognitive status and functional capacity during exacerbation of chronic obstructive pulmonary disease? Chron Respir Dis 2015;12(3):247–55. [DOI] [PubMed] [Google Scholar]

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