Lung disease as a determinant of cognitive decline and dementia

One of the most common causes of impaired lung function is chronic obstructive pulmonary disease (COPD), a preventable and treatable disease characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases, most commonly tobacco smoke [11]. Unlike other common chronic diseases, the global prevalence of COPD has increased in recent years. In the UK, 10% of adults have an abnormally low FEV1 and 210 million people are diagnosed with COPD around the world. COPD is projected to become the third leading cause of death by 2030 [12], with smoking cessation the most effective intervention to reduce the risk of developing COPD and prevent disease progression [13,14]. Associations between COPD and cognitive function are explored in detail below.

It is estimated that 300 million people suffer with asthma globally, with prevalence rates of around 15.3% in England [15]. Asthma is defined clinically by the presence of symptoms (more than one of wheeze, breathlessness, chest tightness, cough) and of variable airflow obstruction. Unlike COPD, asthma predominantly affects children and young adults; it is most commonly associated with atopy and inflammation (allergy, eczema and hayfever) rather than smoking exposure.

Several studies suggest an association between neurocognitive dysfunction and asthma, citing mechanisms such as sleep disturbance, medication effects and systemic inflammation [16-26]. Mid-life asthma in particular has been associated with incidence of cognitive impairment and dementia (hazard ratios of 1.88 and 1.27, respectively), with risks increased further with exacerbation and hospitalisations [23-26]. In a study of 46 atopic patients with asthma, cognitive function was measured at baseline and 6 weeks after inhaled bronchodilators and steroids. This showed an improvement in cognition which appeared to relate to an improvement in variability of lung function, although it is not clear that practice and regression to the mean effects were fully accounted for [24]. A similar number of studies suggest no significant association between asthma and cognitive impairment [27-31]. The Childhood Asthma Management Program involved 1,041 children aged 5 to 12 years with asthma who were assessed prior to randomisation to receive anti-inflammatory medications. Neurocognitive performance was found to be normal and not associated with measures of asthma severity [27]. Flannery and colleagues [30] examined cognitive function in 11,578 children and found little support for a link between asthma and neurodevelopment problems. There were mixed results from an analysis of the Swedish Twin Registry, which showed a very modest longitudinal association between atopy and dementia (hazard ratio 1.16) in a large study of 22,188 people [20].

In many of these studies, sample sizes and multiple confounders in case definition limit definitive interpretation, leading some authors to conclude that socio-economic factors are mainly responsible for the variation in school performance and neurocognitive ability in asthma [32].

It is widely accepted that patients with COPD suffer with systemic manifestations beyond the lung and that these impact on disease management and further impair functional capacity, health-related quality of life and prognosis [33,34].

A UK study confirmed that COPD is associated with numerous co-morbidities; 2,699 patients with COPD in a UK General Practice research database were compared with age- and gender-matched controls. Amongst COPD patients, there was more frequent angina, cataracts, bone fractures and osteoporosis [35]. Importantly, these co-morbidities seem to be independent of smoking and traditional risk factors, suggesting a ‘COPD specific’ effect [36,37]. In addition it is thought that other frequently observed co-morbidities, including musculoskeletal weakness, diabetes, and depression, cannot be easily attributed to smoking [38].

The presence of these co-morbidities has a significant negative impact. In an analysis of over 20,000 subjects pooled from the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study, an increasing number of co-morbidities was associated with a significantly increased risk of death at all stages of COPD severity. In addition, risk of hospitalisation within 5 years was increased in the presence of a number of co-morbidities including diabetes, hypertension and cardiovascular disease [39,40].

Estimates of cognitive dysfunction in COPD range from 10 to 61%, depending on the study population and method of neuropsychological assessment [4,41]. Cognitive impairment appears to be an important determinant of outcomes in COPD, with evidence that it is associated with poor quality of life, hospitalisation and reduced survival and is likely to profoundly influence an individual’s ability to manage their disease [4,42,43].

A 12 month retrospective database analysis of 126,106 US nursing home residents showed a concurrent diagnosis of COPD and dementia in 37.2%, and 62% of those with COPD also had short-term memory problems [44]. Moderate to severe cognitive impairment has been shown to be present in up to 61% of severely hypoxaemic individuals with COPD [41]. The majority of studies show that patients with COPD have either global impairment or deficits in attention, memory and learning and motor functions. In the combined Nocturnal Oxygen Therapy and the Intermittent Positive Pressure Breathing trials 42% of patients with COPD had moderate to severe cognitive impairment compared with 21% amongst the control group [45]. A large longitudinal study showed that self-reported diagnosis of severe COPD (defined by oxygen use or physical activity limitation) was associated with a more rapid decline in a questionnaire marker of cognitive performance over 6 years [46].

In a well conducted cross-sectional analysis, MCI was found in 36% of patients with moderate to severe COPD (versus 12% in controls) [47]. Two longitudinal studies quantify the risk of developing MCI in patients with COPD. The first found that a diagnosis of COPD in mid-life is independently associated with developing cognitive impairment in later life (hazard ratio 1.85) [23]. The other found that a diagnosis of COPD at baseline was associated with an 83% increased risk of non-amnesic MCI (hazard ratio 1.83 (95% confidence interval 1.04 to 3.23)) [48]. In addition there was a dose–response relationship between individuals with COPD duration of over 5 years at baseline and risk of MCI [48].

By contrast, two studies reported no significant cognitive impairment in COPD. In one, patients with mild hypoxaemia had worse verbal fluency compared with a control group, but not outside the normal range [49]. The other compared community-based COPD patients and a healthy group; no difference in Mini Mental State Examination (MMSE) was reported, although the COPD group may have also included cases of asthma - and MMSE does not measure executive or working memory functions [50].

In summary, COPD is consistently associated with an increase in the risk of cognitive impairment, cognitive decline and dementia. The severity and frequency appear more marked in those with more advanced disease.