Dodd Alzheimer's Research & Therapy (2015) 7:32 DOI 10.1186/s13195-015-0116-3 REVIEW Open Access Lung disease as a determinant of cognitive decline and dementia James W Dodd Abstract Almost 40 million people currently live with dementia but this is estimated to double over the next 20 years; despite this, research identifying modifiable risk factors is scarce. There is increasing evidence that cognitive impairment is more frequent in those with chronic lung disease than those without. Chronic obstructive pulmonary disease affects 210 million people, with cognitive impairment present in 60% of certain populations. Co-morbid cognitive dysfunction also appears to impact on important outcomes such as quality of life, hospitalisation and survival. This review summarises the evidence of an association between cognition, impaired lung function and obstructive lung disease. It goes on to examine the contribution of neuro-imaging to our understanding of the underlying pathophysiology. While the mechanisms of brain pathology and cognitive impairment are likely to be complex and multi-factorial, there is evidence to suggest a key role for occult cerebrovascular damage independent of traditional vascular risk factors, including smoking. Introduction those with lung disease (that are already known to nega- The World Health Organization reports that 35.6 million tively impact on cognition, such as smoking and hyperten- people currently live with dementia but this is estimated sion) and/or as a direct result of respiratory limitations to double over the next 20 years; despite this, research (such as hypoxaemia). Figure 1 summarises some of the identifying modifiable risk factors is scarce. Mild cognitive overlapping risk factors for cognitive impairment in both impairment (MCI) is associated with a 5 to 10% annual general and chronic lung disease populations. However, conversion rate to dementia [1,2]. However, MCI is con- importantly it seems that there is an association between sidered a potentially reversible state and not all of those cognitive impairment and lung disease independent of with MCI go on to develop dementia. Therefore, clarifying these factors [4]. which features predict progression to dementia and Lung function is most often measured by spirometry, identifying modifiable targets is currently of great inter- giving forced expiratory volume in 1 second (FEV1) and est. The diagnosis of MCI generally requires the exclu- forced vital capacity, standardised for age and gender. sion of co-morbid illness but there have been concerns The association between lung function and cognition about the generalisability of this approach given that has been tested in a number of large healthy population 50%ofthosewithMCIarethoughttohaveamedical studies, particularly in elderly groups [4]. The majority of co-morbidity [3]. Chronic lung disease is one such medical studies support at least some independent association be- co-morbidity with increasing evidence of an association tween lung function and cognitive performance (Table 1). with cognitive dysfunction and brain pathology. The most comprehensive study comes from a longitu- dinal analysis of over 10,000 healthy men and women with repeated cognitive assessments between 1990 and 2006. Lung function and cognitive impairment This showed that impaired lung function was independ- Individuals with chronic lung disease are thought to be ently associated with worse cognitive function at baseline at an increased risk of cognitive decline. This may be as and higher subsequent risk of dementia hospitalization. a result of risk factors which occur more frequently in However, no association was found between lung function and cognitive decline over time [5]. Other studies have Correspondence: [email protected] Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Learning & Research Building, Southmead Hospital, Bristol, BS10 5NB, UK © 2015 Dodd; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dodd Alzheimer's Research & Therapy (2015) 7:32 Page 2 of 8 shown mixed results, and where significant associations have been found they are not universal [6]. For example, mid-life lung function predicts mid-life psychomotor ability, memory, processing speed and executive func- tion, but only psychomotor ability declined significantly over time [7,8]. Age is understood to be the most sig- nificant predictor of cognition and FEV1 also declines with age. However, FEV1 has been shown to be signifi- cantly and independently associated with cognitive function in all ages groups, though correlations can be weak [9,10]. Overall it appears that lung function is independently associated with measures of cognition and rate of cognitive decline. A lack of standardised neuropsycho- logical assessments and variability in adjustment for Figure 1 Risk factors for cognitive impairment in both general confounders between studies currently limit clinical and chronic lung disease populations. This material has not been interpretation. reviewed by the European Respiratory Society prior to release; therefore, the European Respiratory Society may not be responsible Obstructive lung diseases for any errors, omissions or inaccuracies, or for any consequences Chronic obstructive pulmonary disease arising therefrom, in the content. Reproduced with permission of the European Respiratory Society [4]. One of the most common causes of impaired lung func- tion is chronic obstructive pulmonary disease (COPD), a preventable and treatable disease characterised by Table 1 Lung function and cognition Study design Population Comment Reference Longitudinal cohort N = 10,975 men + women aged Reduced lung function was associated with worse [5] 1990-2005 47–70 years. Atherosclerosis Risk performance in cognitive assessments and with an in Communities (ARIC) Study increased risk of dementia hospitalization. No association was found between lung function and cognitive decline over time Vietnam veteran study N = 4,256 men aged 20 years Poor cognitive ability in mid-life associated with [9] reduced lung function in mid-life. Effects size small. Similar effects in non-smokers Prospective observational N = 864 normative aging study. Baseline FEV1 associated with visuo-spatial and [6] study 12 year follow-up global ability. Higher FEV1 associated with slower decline only in attention. Rate of decline in FEV1 not associated with cognition. Overall limited evidence of a relationship between FEV1 and cognitive decline The Age, Gene/Environment N = 3,635; N = 1,281 subset 2/3 Low mid-life FEV1/height predicted poor memory, [8] Susceptibility Reykjavik Study: serial FEV1 over 7.8 years processing speed, executive function MCI and 23 year follow-up dementia 23 years later. Decline in lung function over 7.8 years in mid-life was not associated with MCI or dementia Longitudinal population N = 832 (50–85 year olds); Changes in lung function led to subsequent [83] Swedish Twin Study 19 year follow-up changes in psychomotor speed and spatial abilities. No evidence that declines in cognitive function lead to subsequent decline in lung function Longitudinal 23 year follow-up N = 3,036 Japanese American Baseline FEV1 predict cognitive function (Cognitive [84] males in Hawaii Abilities Screening Instrument - CASI) Healthy Longitudinal All ages N = 2,551 FEV1 associated with cognitive function in all age [10] groups, although significant associations were weak MRC National Survey of N = 1,778 men and women Mid-life FEV1 associated with mid-life psychomotor [7] Health and Development speed and decline over 10 years FEV1, forced expiratory volume in 1 second; MCI, mild cognitive impairment; MRC, Medical Research Council. Dodd Alzheimer's Research & Therapy (2015) 7:32 Page 3 of 8 persistent airflow limitation that is usually progressive Twin Registry, which showed a very modest longitu- and associated with an enhanced chronic inflamma- dinal association between atopy and dementia (hazard tory response in the airways and the lung to noxious ratio 1.16) in a large study of 22,188 people [20]. particles or gases, most commonly tobacco smoke In many of these studies, sample sizes and multiple [11]. Unlike other common chronic diseases, the glo- confounders in case definition limit definitive interpretation, bal prevalence of COPD has increased in recent leading some authors to conclude that socio-economic years. In the UK, 10% of adults have an abnormally factors are mainly responsible for the variation in low FEV1 and 210 million people are diagnosed with school performance and neurocognitive ability in COPD around the world. COPD is projected to be- asthma [32]. come the third leading cause of death by 2030 [12], with smoking cessation the most effective inter- Chronic obstructive pulmonary disease - a multi system vention to reduce the risk of developing COPD and disease prevent disease progression [13,14]. Associations be- It is widely accepted that patients with COPD suffer tween COPD and cognitive function are explored in with systemic manifestations beyond the lung and that detail below. these impact on disease