Cognitive impairment in COPD: an often overlooked co-morbidity

KEYWORDS:

• COPD
• cognitive impairment
• cognition
• co-morbidity
• multi-morbidity

1. Introduction

Chronic Obstructive Pulmonary Disease (COPD) is characterized by multiple co-morbidities, such as cardiovascular disease, diabetes, depression, and osteoporosis [1]. However, co-morbid neurocognitive damage and dysfunction are frequently overlooked despite a growing body of well-conducted cross-sectional and longitudinal studies pointing to a frequent and important association with COPD and impaired lung function. A diagnosis of mild cognitive impairment (MCI); when deficits develop in cognitive domains, is important since it is known to be associated with worse outcomes and increased healthcare burden in COPD [2]. A diagnosis of MCI is considered a precursor to a diagnosis of dementia with a reported 5–10% annual conversion rate, but crucially MCI is also considered a potentially reversible state, with some individuals who are diagnosed with MCI subsequently returning to normal cognitive function [3]. Therefore, it is a health priority to clarify risk factors both for MCI and progression to dementia. Although epidemiological research suggests that COPD increases the risk of cognitive impairment, establishing causality is challenging. Various pathological mechanisms are hypothesized including hypoxia and structural brain changes. In this expert opinion, we will discuss evidence for the association of COPD and cognitive impairment, possible underlying mechanisms, the impact on morbidity and mortality, and suggest how future research could help us understand and manage this common and important co-morbidity.

2. Epidemiological evidence linking COPD and cognitive impairment

Most observational epidemiological research suggests COPD is associated with an increased risk of cognitive impairment, although estimates vary. A literature review of 17 studies estimated a prevalence of cognitive dysfunction in COPD ranging from 10% to 61% [3]. A systematic review found 8 of 12 studies reported increased cognitive dysfunction with worsening COPD severity [4]. Finally, longitudinal work has also demonstrated that COPD can influence the risk of developing MCI, with midlife obstructive lung disease found to be associated with increased risk of developing of Alzheimer’s or MCI; Odd Ratio (OR) 1.33 (95% CI, 1.07–1.64) [5].

The pattern of cognitive impairment has also been studied, with evidence of a global impairment in some groups, whilst others show a COPD specific pattern of deficits in attention, memory, learning, and motor functions [3]. As the extent and pattern of cognitive deficits vary, multiple psychometric tests are required for full evaluation in research and clinical practice [6].

Methodological errors may also be contributing to these mixed results, for example, observational studies often lack a matched smoking control group, despite smoking being an important risk factor for cognitive impairment. Case control studies are often limited by small numbers of participants weakening power. However, increasing statistical power through meta-analyses of data is not always possible due to a combination of differing diagnostic criteria, cognitive assessments, heterogenous sample populations, and poor outcome definitions.

3. Hypothesis for mechanism linking COPD with cognitive impairment

The exact etiological link between COPD and cognitive impairment remains unknown. Proposed casual mechanisms include hypoxia-mediated neuronal damage or reduction in neurotransmitters that require oxygen-dependent enzymes for synthesis. However, a meta-analysis of nine studies found a negative correlation between PaO₂ and cognitive function (with a pooled r = 0.405, 95% CI 0.31–0.55), and cognitive deficits have been found in both hypoxic and non-hypoxemic patients with COPD [7,8]. Acute supplemental oxygen therapy does not appear to impact cognitive function, and whilst long-term oxygen has been shown to improve cognition, it is dependent on which cognitive test is being used [9,10]. Therefore, although hypoxia may explain some cognitive deficit, other factors are important. The relationship with carbon dioxide is even less clear with some studies showing a relationship with executive function, attention, and verbal memory with others showing no relationship [8].

Other plausible mechanisms have been proposed to explain why patients with COPD may be at an increased risk of brain damage and dysfunction, including increased systemic inflammation, oxidative, and physiological stress [11]. It is therefore reasonable to consider that cognitive impairment in COPD may be mediated through increased cerebrovascular damage. However, some neuroimaging studies suggest that the pattern of vascular brain disease seen in COPD may be different to that of ischemic cerebrovascular disease and vascular dementia, and may not be explained by cardiovascular risk and smoking alone. While cerebral white matter lesions (usually a marker of cerebrovascular pathology) are seen in COPD, these changes appear to have a greater link with anxiety and depression rather than significant cognitive impairment [12]. It has also been suggested that microvascular rather than macrovascular damage has a greater part to play in COPD. Support for this comes from a small but detailed case control study showing increased retinal microvascular changes in COPD patients compared to smoking controls, independent of standard cardiovascular risk factors [13].

It is important to consider the effect of smoking since it increases the risk of both COPD and vascular brain disease. We know that MRI’s of smokers brains reveal increased periventricular white matter hyperintensities with a dose-dependent like relationship with greater pack/years [14]. However, after adjusting for smoking, lung function remains associated with increased white matter brain lesions and risk of cognitive impairment. This suggests that like hypoxemia, smoking does not explain all the brain changes and cognitive impairment linked with COPD and lung function [15,16].

Acute exacerbations of COPD are frequent, life threatening, and complex heterogenous events characterized by acute infection, hypoxemia, physiological and psychological stress. All these factors are likely to influence cognition, but efforts to assess cognition during exacerbation and after recovery have been limited. During acute exacerbations patients with COPD have been found to have worse cognitive impairment than similar patients with acute heart failure [17]. This acute cognitive deterioration is seen to improve over 6 weeks in most, but not in all patients [18]. Whether exacerbations change cognition in the long term is unclear [19].

Efforts to increase physical activity may positively impact cognition in patients with COPD. Proposed mechanisms include decreasing oxidative stress, reducing systemic inflammation, and improving microvascular circulation [20]. Reduced mobility may also contribute to social isolation, anxiety, and depression potentially contributing to progressive cognitive impairment. Exercise programs to improve cognition have been studied; however, a meta-analysis of trials is not possible due to heterogeneity of studies, typifying research issues in this field [21]. It remains uncertain if pulmonary rehabilitation and exercise classes will improve cognition.

4. Impact of cognitive impairment in COPD

Whilst efforts to fully understand the causal and etiological relationship between COPD and cognition is ongoing, the impact on clinical outcomes and morbidity is clear. Impairment in memory, cognitive flexibility, and visual processing may have direct impact on COPD patients’ ability to self-manage their disease [6]. Studies have shown greater disability, risk of exacerbation, and poorer medication compliance in those with cognitive impairment [2,8,22]. The effect of cognitive impairment on mortality in COPD is less certain. Cognitive dysfunction is associated with increased mortality in acute hospital admissions even in those without COPD, but its effect specifically in the COPD population has not been well studied and available results are mixed [8]. A large prospective study in COPD found no link between mortality and Mini Mental State Examination (MMSE), whilst another study found drawing impairment was a risk factor for mortality in those with severe COPD [8,23].

5. Five-year view

Despite decades of research, our understanding of cognitive impairment in COPD remains incomplete. Most studies are in small populations, often repeating previous study methodologies but with different cognitive tests. Other studies examine narrow putative pathological processes, even though we are yet to ascertain if COPD directly causes increased risk of cognitive impairment. Given the significant-shared risk factors, even after adjustment for confounders, traditional observational studies will not determine causality. Novel epidemiological techniques to infer causality such as Mendelian Randomization offer the opportunity to explore this important gap in our knowledge.

Our understanding of COPD pathogenesis is also evolving, which in turn should change the way that we think about the relationship between COPD and its co-morbidities. It is becoming clear that COPD and lung function decline is not simply due to smoking, but early life factors significantly affect lung development and lung function trajectories. Available data suggests a link between impaired lung function and cardiovascular co-morbidity as early as the third decade [24]. More work is therefore needed to see if, when, and to what extent, cognitive deficits are associated with these abnormal lung function trajectories.

Large consortiums and birth cohorts will provide bigger, longitudinal samples to facilitate more powerful epidemiological research and trajectory analysis in well-phenotyped cohorts.

6. Summary

Whilst it remains unclear if COPD causes cognitive impairment, and what the underlying mechanisms could be, there is an association between COPD and cognition which is harmful to this vulnerable population. Too often observational analysis of prevalence and underlying mechanism are repeated, without providing definitive conclusions. We welcome research designed to evaluate causality of the relationship and suggest use of Mendelian Randomization. However, if the association is not found to be causal, but is the result of shared environmental, genetic, or behavioral processes it is important to not overlook the impact of impaired cognition on people living with COPD. Research to discover pharmacological and non-pharmacological interventions to manage cognitive impairment in both acute and stable COPD patients should also be prioritized.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Medical Research Council (MC_UU_00011/11) and MRC CARP Fellowship.