Chronic Obstructive Pulmonary Disease as a Risk Factor for Cognitive Dysfunction: A Meta-Analysis of Current Studies

Abstract

Cognitive dysfunction has been shown to be associated with many risk factors, such as smoking, diabetes, and body mass index. Chronic obstructive pulmonary disease (COPD), a common disease within the elderly population, has also been found to be related to cognitive decline. However, whether COPD is a risk factor of cognitive dysfunction is not well established. The purpose of this meta-analysis is to investigate the role COPD plays in cognitive dysfunction. PubMed, Cochrane library and Web of Science databases were searched. Three cohort studies and eleven cross-sectional studies were found to be eligible. According to our results, COPD patients had a higher risk of cognitive dysfunction than controls (OR [odds ratio]: 1.72; 95% CI, 1.12–2.65; p = 0.01). The exacerbation of COPD was strongly correlated with cognitive decline. COPD patients performed worse than controls on the Mini– Mental State Examination test, but the results were not statistically significant (OR: –0.79; 95% CI, [–1.78, 0.19]; p = 0.11). Thus, more attention should be given to the occurrence of cognitive decline in COPD patients. The prevention and control of COPD exacerbation are critical.

Keywords

Chronic obstructive pulmonary disease cognition dementia meta-analysis

INTRODUCTION

Cognitive dysfunction results in poor memory, interruption of daily activities, and emotional abnormalities. The incidence of cognitive dysfunction is growing at alarming rates in all regions of the world and is related to population aging [1]. Cognitive dysfunction is a burden on the affected patients, families, and society at large.

The risk factors that have been reported include age, genetics, education, cerebral trauma, obesity, smoking, alcohol, mid-life hypertension, stroke,diabetes, hyperlipidemia, myocardial infarction, and heart failure [2 –6].

Chronic obstructive pulmonary disease (COPD) is characterized by partially reversible airflow limitations and progressive inflammation of the airway [7]. Researchers have shown that COPD has a potential influence on cognitive impairment [8 –12]; however, the results have been inconsistent [13 –16].

Schou et al. published a relevant systemic-review in 2012 [17]. They analyzed fifteen clinical trial results and concluded that cognitive function was impaired in patients with COPD compared to healthy controls. As additional studies have been carried out more recently, a meta-analysis is necessary to estimate whether COPD plays a role in cognitive dysfunction.

METHODS

The literature-search strategies, inclusion and exclusion criteria, outcome measurements, and methods of statistical analysis were completed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology recommendations for study reporting [18 –20]. All analyses were based on previously published studies; thus, ethical approval and patient consent were not required.

Literature-search strategy

To identify relevant studies, PubMed, Web of Science, and Cochrane library databases were searched through to June 2015 without restriction of language or publication type. The following terms were searched in the title and/or abstract: Dementia, MCI, cognition, cognitive impairment, cognitive dysfunction, COPD, and chronic obstructive pulmonary disease. The search was conducted and reviewed independently by two authors (Zhang and Cai) to improve searching quality. The reference lists of the included studies were screened to find the relevant studies. When multiple reports studying the same group of participants were published, the latest one was included. The search, inclusion and exclusion processes are shown in Fig. 1.

Inclusion and exclusion criteria

To ensure homogeneity across studies, the included studies had to meet specific criteria. First, all available comparative studies (prospective or retrospective cohort studies, case-control studies, and cross-sectional studies) had to include a COPD group and healthy control group. Second, the diagnosis of COPD had to be made according to either the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines or the International Classification of Diseases (ICD). Third, cognitive assessment had to be conducted using at least one of following methods: a) ICD; b) Certain acknowledged diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) or the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA); c) Specific clinical features and cognitive tests that were used in clinical diagnosis; and/or d) MMSE score. Studies were excluded when participants exhibited other neurological degenerative, psychiatric or other diseases that may be able to influence cognitive function directly. Review articles, case reports, editorials, letters to editorials and animal experimental studies were also excluded.

Data extraction and outcomes of interest

Data from the included studies were extracted and summarized independently by two of our authors (Zhang and Cai). Any disagreements were resolved by the senior authors (Fang and Zheng).

The primary outcomes were the comparison of risk of cognitive dysfunction and the comparison of the mean value of the MMSE score in two study groups. The secondary outcomes were as follows: 1) the comparison of the MMSE score between stable COPD and control groups and; 2) the comparison of the MMSE score between acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and stable COPD groups.

Quality assessment and statistical analysis

The quality of cohort studies was assessed by the Cohort Studies Version of Newcastle-Ottawa Quality Assessment Scale [21], which consists of three factors: Patient selection, comparability of the study groups, and assessment of outcome. A score of 0–9 was allocated to each study. Studies that achieved six or more stars were considered to be of high quality. The quality of cross-sectional studies was assessed by the Agency for Healthcare Research and Quality Scale. This scale consists of eleven questions and a score of 0–11 was allocated to each study. Studies that achieved seven or more stars were considered to be of high quality.

All of the meta-analyses were performed using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). The weighted mean difference and odds ratio were used to compare continuous and dichotomous variables, respectively. All results were reported with 95% confidence intervals (CIs).

Statistical heterogeneity between studies was assessed using the chi-square test with significance set at p < 0.10, and heterogeneity was quantified using the I² statistic. The random-effects model was used if there was heterogeneity between studies; otherwise, the fixed-effects model was used [22]. Sensitivity analysis was performed in each comparison.

RESULTS

Fourteen studies, including 64,272 cases (22,524 for COPD and 41,748 for controls) fulfilling the predefined inclusion criteria, were included in the final analysis (Fig. 1). All publications were full-text articles. Agreement between the two reviewers was 97% for study selection and 93% for quality assessment of trials.

Characteristics of eligible studies

The characteristics of the included studies are shown in Table 1. Among them, there were two prospective cohort studies [23, 24]; one retrospective cohort study [25]; and eleven cross-sectional studies [15 , 26–34]. Three studies included both the AECOPD group and stable COPD group [26 , 30]. One study focused only on AECOPD [29]. Two studies measured stable COPD [16, 23]. One article was written in Turkish [31], and the others were in English. The diagnostic criteria used are listed in Table 1.

Methodological quality of included studies

The quality of the included studies was generally low. Three studies were cohort studies that all scored six stars or more and one of them had a relatively small sample size [23]. All of the studies clarified the length of patient follow-up. Eleven studies were cross-sectional studies, with five studies achieving seven or more stars. The matching criteria in each study were variable. The sample sizes were generally small in the cross-sectional studies. The results of meta-analysis of each comparison were listed in Table 2.

Primary outcomes

Comparison of risk of cognitive dysfunction between COPD and control groups

Six studies [15 , 33] assessed the risk of cognitive dysfunction in 63,462 patients, and the data showed a significantly higher risk in the COPD group compared to the control group (OR: 2.14; 95% CI, 1.19–3.86; p = 0.01) (Fig. 2). There was statistically significant heterogeneity across these six studies (Chi² = 16.36, df = 5 [p = 0.006]; I² = 69%). Five of the six studies were recognized as high-quality studies according to the previously described criteria [15 , 33]. Assessment of the high quality studies also revealed a significantly higher risk for cognitive dysfunction in the COPD group (OR: 1.72; 95% CI, 1.12–2.65; p = 0.01), though the heterogeneity among the high quality studies was significant (Chi² = 8.01, df = 4 [p = 0.09]; I² = 50%). Thesemeta-analysis results indicate that patients with COPD are more susceptible to cognitive impairment than non-COPD controls.

Comparison of MMSE scores between COPD and control groups

Eleven studies assessing 1,415 patients listed the mean value of the MMSE score in both groups[15 , 34]. Nine studies listed the standard deviation (SD). Two studies only gave the interquartile range [26, 30]; therefore, we emailed the authors in efforts to obtain raw data from these two studies but received no replies. Therefore, for these two studies, we had to calculate the SD values ourselves using statistical methods. The data from the eleven studies showed a significantly lower MMSE score in the COPD group than the control group (OR: –1.99; 95% CI [–3.02,–0.97]; p = 0.0001) (Fig. 3), and the heterogeneity was significant (Chi² = 130.08, df = 10 [p < 0.00001]; I² = 92%). Among all of the eleven studies, five were recognized as high-quality studies of 961 patients in one cohort study [23] and four cross-sectional studies [15 , 31]. Assessment of these five high-quality studies showed a lower MMSE score in the COPD group than the control group, but it was not significant (OR:–0.79; 95% CI [–1.78,–0.19]; p = 0.11); however, the heterogeneity among them was significant (Chi² = 20.97, df = 4 [p = 0.0003]; I² = 81%).

Secondary outcomes

Some studies were inconclusive about whether the exacerbation of COPD was associated with cognitive decline; therefore, we conducted a meta-analysis to conclusively determine this. AECOPD diagnosis means that there is deterioration of stable COPD over a short period of time. Patients with AECOPD always need hospitalization. Stable COPD is defined by the absence of symptom exacerbation within a time period generally not less than the preceding 8 weeks. We have listed the diagnostic criteria of the two COPD states in Table 3.

Comparison of the MMSE score between stable COPD and control groups

Three studies included an AECOPD group, stable COPD group and control group [26 , 30]. Two studies focused only on stable COPD [16, 23]. Together, these five articles recorded the MMSE scores of 480 patients. The results indicated that patients in the stable COPD group performed worse in MMSE than the control group, but the difference was not significant (OR: –0.94; 95% CI [–2.13,0.25]; p = 0.12) (Fig. 4), while the heterogeneity among these studies was significant (Chi² = 46.17, df = 4 [p < 0.00001]; I² = 91%). As three of the five studies were of high quality [16 , 30], we evaluated the results but no significant differences were discovered (OR: –0.12; 95% CI [–0.51, 0.27]; p = 0.55), although the heterogeneity among the three high-quality studies was found to be significant (Chi² = 3.45, df = 2 [p = 0.18]; I² = 42%).

Comparison of the MMSE score between AECOPD and stable COPD groups

There were three studies that mentioned the difference in cognitive changes between AECOPD patients and stable COPD patients, including a total of 309 patients [26 , 30]. The meta-analysis results of these studies showed that patients with AECOPD performed worse on MMSE tests than patients with stable COPD, and the difference was significant (OR:–1.65; 95% CI [–2.27,–1.03]; p < 0.00001) (Fig. 5), although the heterogeneity among them was not significant (Chi² = 1.86, df = 2 [p = 0.39]; I² = 0%). There was only one high quality study among the three; therefore, we did not need to assess the one study separately.

Sensitivity analysis and publication bias

Sensitivity analysis was made in comparison with significant heterogeneity among studies (Table 4).

In the comparison of risk of cognitive dysfunction and in the comparison of MMSE scores between stable COPD and control groups, the heterogeneity among studies was significant. After excluding the relatively low-quality studies, the same results were obtained. So we can conclude that the sensitivity is low and that the results are reliable.

In the comparison of MMSE scores between COPD and control groups, the heterogeneity among the studies was significant. The results of all included studies showed significantly lower MMSE scores in the COPD group in comparison to the control group. The results of high-quality studies showed lower MMSE scores in the COPD group compared to the control group, but the results were not significant. After the low-quality studies were excluded, the trend of the results was the same but with different levels of significance; so the results of the MMSE score comparison between COPD patients and controls are not steady relatively.

As there are less than 10 high-quality studies in each comparison in our meta-analysis, a publication bias assessment cannot be performed accurately. However, we completed a funnel plot to estimate publication bias. Figure 6 shows a funnel plot of the studies included in each comparison. Publication bias existed in the comparison between the MMSE scores of COPD and control groups; however, no significant publication biases were observed in othercomparisons.

DISCUSSION

In our meta-analysis, we obtained the following points: 1) the COPD group had a higher risk of cognitive decline than the control group; 2) the mean MMSE score was lower in the COPD group than the control group but without statistical significance; 3) the mean MMSE score was lower in the mild COPD group than the control group but without statistical significance; and 4) the mean MMSE score was significantly lower in the AECOPD group than the stable COPD group.

According to these results, we can conclude that patients with COPD are susceptible to cognitive dysfunction. AECOPD has a strong correlation with cognitive decline, and this indicates that clinicians should pay close attention to the occurrence of cognitive decline in COPD patients. Further, it suggests that preventing and effectively treating COPD exacerbation are necessary steps toward the prevention of cognitive dysfunction. Additional work is needed to determine which types of treatment can effectively slow the progression of cognitive decline in COPD.

Pulmonary disease was found to be related to cognition in the early 1980s [35]. Most researchers proposed that hypoxemia was the factor connecting COPD and cognitive dysfunction [36]. However, numerous studies have reported multiple factors that contribute to this process, including systemic inflammation [37, 38], hypercapnia [8, 39], oxidative stress, hypoperfusion [40, 41], physical activity [8 , 42–46], shared risk factors, such as smoking [47], and shared comorbidities, such as hypertension and diabetes mellitus [30]. Some articles even demonstrated that COPD was an independent predictor of dementia [14, 41].

In 2012, Schou et al. completed a systemic review to illustrate the relationship between COPD and cognitive dysfunction [17]. They analyzed fifteen different articles about clinical observations. The included criteria used by the Schou et al. study were almost completely different in comparison to our current meta-analysis study. Interestingly, while our studies had minimal overlap in the inclusion of articles as a result, the findings in our study were discovered to support those of the Schou et al. study.

We summarized the articles that used the MMSE test. The MMSE test can examine short-term memory, calculation, orientation, and verbal function. It is an easy test to conduct, and the cut-off value of 24 points has a good specificity for measuring cognitive dysfunction. The MMSE is the most widely used cognitive test in clinical practice. Although we discovered that the prevalence rate was higher in the COPD group compared to the control group, as a continuous variable, the MMSE score did not show a significant difference. This may be because the MMSE test is not sensitive enough to identify the extent of severity of cognitive dysfunction. Perhaps other test batteries would be better suited to illustrate continuous changes in the cognitive state.

Certain limitations may have influenced the precision of our meta-analysis as follows: 1) the diagnostic methods were not the same in the different studies analyzed, and this may have introduced bias; 2) the matched comorbidities or variables were different in each study; 3) the general quality of the included studies was relatively low; 4) we only assessed the MMSE test alone but did not analyze other test batteries separately; 5) our meta-analysis contained both cross-sectional studies and cohort studies; and 6) publication bias existed in our analyses although we applied multiple strategies to identify studies, including eliminating language restrictions. Together, all of these limitations may affect the interpretability of our article.

Nonetheless, based on our results, we can conclude that COPD patients have a higher risk of cognitive dysfunction. The authors in one longitudinal study observed that mid-life COPD was more closely related to a high prevalence of cognitive dysfunction than late-life COPD [48]. Thus, according to this study, COPD precedes and may be causative of cognitive dysfunction. To prove a causative relationship, more prospective and long-term clinical studies are needed. We acknowledge that these types of prospective studies are time-consuming and difficult to complete, but the results are very powerful.

Conclusion

Overall, the results from this meta-analysis showed that the risk of cognitive dysfunction was higher among people with COPD than in people without COPD (OR: 1.72; 95% CI, 1.12–2.65; p = 0.01). Further, the exacerbation of COPD was found to be strongly correlated with cognitive decline.

Footnotes

ACKNOWLEDGMENTS

This study was supported by grants from the Science and Technology Program of Guangzhou, China (Grant No. 201508020026).

Authors’ disclosures available online ().

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