Abstract
Introduction: Various cognitive deficits associated with reduced pulmonary function are reported in different studies, but the pattern of cognitive deficits across multiple domains and its associated everyday functional disability remain unclear. Methods: We analyzed neuropsychological functioning, cognitive impairment and accompanying disability in instrumental activities of daily living (IADL) associated with reduced pulmonary function in community-living middle-aged and older adults in Singapore. Performance on a comprehensive battery of neuropsychological tests, spirometry and cognitively demanding IADLs were assessed in the population-based Singapore Longitudinal Ageing Studies. Results: Consecutive 10% increase in forced expiratory volume in 1 s (FEV1) as percent of predicted was positively associated with 0.18 points increase in Mini-mental state examination (MMSE) and 0.04 points increase in executive function, independent of age, education and other variables. Subjects with moderate-to-severe airway obstruction showed significantly poorer MMSE score (p for linear trend = 0.001), and information processing speed (p for linear trend < 0.001). FEV1 (per 10% of predicted) was significantly associated with lower risk of cognitive impairment (OR = 0.92, 95% CI: 0.87-0.98, P = 0.005) and cognitive IADL disability (OR = 0.86,95% CI:0.79–0.93, P < 0.001). Pulmonary restriction was associated with greater risk of cognitive impairment (OR = 1.98, 95% CI: 1.26-3.11, P = 0.003) and cognitive IADL disability (OR = 2.43, 95% CI: 1.31-4.53, P = 0.005). Moderate-to-severe airway obstruction (OR = 2.04, 95% CI: 1.11–3.74, P = 0.022) was positively associated with cognitive IADL disability. Conclusion: The findings suggest a measurable but modest cognitive effect of low pulmonary function that was accompanied by corresponding disability in living activities. The effect on executive functioning should be further investigated in longitudinal studies.
Introduction
Pulmonary function is a salient index of health and has long been used as a biomarker of aging (Citation1). As such, poor pulmonary function has been proposed to be a contributing cause of cognitive decline and impairment in late life (Citation2). In patients with chronic obstructive pulmonary disease (COPD), gross deficits in cognitive functions are observed in domains such as abstract reasoning (Citation3), complex visual motor process (Citation4), and verbal learning (Citation5). Cognitive impairment in COPD patients has also been associated with reduced pulmonary function (Citation6).
Similar associations were reported in population studies of non-diseased older individuals. Cross-sectional studies of middle-age and older persons indicate that forced expiratory volume in 1 second (FEV1) was positively related to cognitive performance on tasks of language (Citation7), attention (Citation8), information processing speed (Citation8-10) and verbal learning and memory (Citation9,10). Furthermore, longitudinal studies showed that poor pulmonary function in middle age influenced cognitive ability in late life (Citation11, 12). Better pulmonary function in midlife has also been shown to be associated with a lower risk of late-life dementia and Alzheimer's disease (AD) (Citation13). Studies suggest that the association of impaired pulmonary function with white matter lesions (WMLs) and lacunar infarcts (Citation14) support the pathological role of chronic hypoxia and ischemic brain damage (Citation15) in explaining the cognitive effect of poor pulmonary function.
A review of the literature shows that positive reports of different cognitive deficits associated with reduced pulmonary function vary between studies depending on the number and domains of cognitive tests employed. Because few studies tested a full range of cognitive domains, the pattern of deficits across multiple domains of cognitive functioning associated with reduced pulmonary function remains poorly understood. An example of note is that there is a lack of information on the possible association of pulmonary function with executive function predicted by the postulated neuropathological mechanism. Furthermore, the ecological and clinical relevance of cognitive deficits associated with reduced pulmonary function reported in studies of community-living older adults is unclear, since none of these studies has concurrently measured the impact of pulmonary function on instrumental activities of daily living (IADL) closely associated with cognitive ability (Citation16).
In the present study, we used cross-sectional baseline data of middle-aged and older participants in the Singapore Longitudinal Aging Study (SLAS) to analyze the relationship between pulmonary function and cognitive performance using a comprehensive battery of neuropsychological tests. We hypothesized that reduced pulmonary function was associated with a pattern of neuropsychological deficits and cognitive impairment accompanied by corresponding disability in cognitively demanding instrumental activities of daily living.
Methods
Population
The participants in this study were identified from the Singapore Longitudinal Aging Study (SLAS), a population-based epidemiologic study of aging and health. A whole precinct sample of all residents (Singapore citizens and permanent residents) in the South East region of Singapore aged 55 years and older was selected for study. Using a complete listing of all households within study precincts, research nurses made house-to-house visits to all households to identify and enroll eligible subjects. Non-participants included those who were unable to complete the interview due to physical or mental frailty such as visual and hearing impairments, aphasia, chronic respiratory failure and profound dementia, those who refused participation and those who were non-contactable. Overall, 2,804 individuals consented to participate, bringing the response rate to approximately 78.2%. The whole sample of study population included 2450 Chinese old adults with complete data on all covariates.
Among them, a random one-in-three subsample of 716 non-demented Chinese participants was selected to undergo a comprehensive battery of neuropsychological tests, and 691 participants who completed at least one of the neuropsychological tests consisted of the analytical sample. The study was granted approval by the National University of Singapore Institutional Review Board. All participants provided written informed consent for enrollment.
Measurements
Cognitive function
Global cognitive function was assessed by Mini Mental State Examination (MMSE) (Citation17), and domain specific cognitive function was assessed by a battery of neuropsychological tests for attention: Digit Span (Citation18) and Spatial Span (Citation19), verbal learning and memory: Rey Auditory Verbal Learning Test (Citation20), visual memory: Visual Reproduction, (Citation19) language: Categorical Verbal Fluency, executive function: Design Fluency (Citation21), and information-processing speed: Symbol Digit Modality Test (Citation22). The neuropsychological tests were administered by trained psychology research assistants in English, Mandarin, or Chinese dialects according to the subject's usual language. The complete battery took 1.5–2 hours to complete. The raw score of each neuropsychological test was transformed into standardized Z score in the study, with high score denoting better cognitive performance. Score of attention was the average of z scores for Digit Span and Spatial Span.
Mini-Mental State Examination (MMSE) with a total score of 30 was administered to measure global cognitive function, including components of orientation, concentration language praxis, and immediate and delayed memory. Lower score indicates poorer performance. The local translated version of the instrument has been evaluated in Singaporean older adults (Citation23) and education-adjusted cutoffs were validated to have high sensitivity and specificity in detecting cases of dementia. In the present study, a uniform cutoff of 23/24 was used to determine cognitive impairment, taking into account the influence of education in the statistical analyses.
Cognitive IADL
Disability in performance on more cognitively demanding instrumental activities of daily living was assessed using the Cognitive IADL score based on 3 activities: using telephone, taking medicine and managing money. The total score of cognitive IADL was the sum of item score for the 3 activities, ranging from 0 to 9. The Cognitive IADL was validated in a previous study and found to be a primary domain of IADL that was more strongly related to MMSE score than the other IADLs (Citation16).
Digit Span
The examiner reads strings of numbers in series with increasing length, and the examinee is asked to repeat the string in the exact order. In Digit Span Backwards, the examinee is asked to repeat the strings in reverse order.
Spatial Span
A computerized version of the Spatial Span test was used; Spatial Forward was performed by having the examinee touch the same square on the computer screen in the same order as they were flashed up (changing from blue to red). In Spatial Backwards, the subject is asked to touch the squares in the reverse order.
Rey Auditory Verbal Learning Test (RAVLT)
The examiner reads a semantically unrelated word list (list A) to the examinee in a series of 5 trials. After each learning trial, the examinee is asked to repeat all the words he or she can remember. A second distracter word list (list B) is then presented. Thirty minutes later, the examinee is asked to recall all the words he or she can remember from list A again.
Visual Reproduction
The examinee is allowed 10 s to observe each of 5 design cards (Citation3 cards with one design and Citation2 cards with Citation2 designs) and reproduce them from memory. Thirty minutes later, the examinee is asked to reproduce the designs again.
Categorical Verbal Fluency
The examinee is asked to produce as many words as possible in one minute from 3 categories (animal, vegetable, and fruit) respectively.
Design Fluency
The examinee draws as many different designs as possible in one minute, while avoiding repeating prior designs, by connecting dots to make different designs with 4 straight lines. In condition 1, there are only black dots presented. In condition 2, there are black and empty dots and the subject is asked to only use the empty dots. In condition 3, the subject is asked to alternate between black and empty dots.
Symbol Digit Modality Test (SDMT)
In the written version of the SDMT, the examinee is asked to transcribe numbers to their corresponding symbol according to a key code provided at the top of the page. Subjects must transcribe as many numbers as possible within 90 s. In the oral version, the examiner records the numbers spoken by the subjects
Pulmonary function
Pulmonary function was performed using a portable, battery operated, ultrasound transit-time based spirometer (Easy-One; Model 2001 Diagnostic Spirometer, NDD Medical Technologies, Zurich, Switzerland) administered by trained nurses according to standard procedures recommended by the American Thoracic Society (Citation24). The FEV1 was expressed as the percentage of predicted values based on sex, age and height from local norms (Citation25). Each participant performed 3 tests and the best of 3 readings of the forced expiratory volume in one second (FEV1) and the ratio of the FEV1 to the forced vital capacity (FVC) was obtained for the study.
Patterns of spirometric performance were categorized as normal (FEV1/FVC ≥ 0.70, FEV1 ≥ 80% predicted and FVC ≥ 80% predicted), restrictive (FEV1/FVC ≥ 0.70, FEV1< 80% predicted or FVC < 80% predicted), and obstructive (FEV1/FVC < 0.70). According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) standard, obstructive airway obstruction was further categorized as mild airway obstruction (FEV1/FVC < 0.70, FEV1 ≥ 80% predicted), moderate airway obstruction (FEV1/FVC < 0.70, 50% ≤ FEV1 < 80% predicted) and severe airway obstruction (FEV1/FVC < 0.70, FEV1 < 50% predicted).
The moderate and severe categories were collapsed given the small number of participants falling within the severe category. FEV1 as percentage of predicted values was analyzed as a continuous independent variable, and categories of severity of airway obstruction was analyzed as categorical polychotomous independent variables in multiple regression models. Whereas analyses of specific cognitive domain tests were based on varying sample size due to incomplete testing and missing values, MMSE data was analyzed for the whole sample.
Covariates
Demographic information collected included age, gender and level of education (primary and below versus higher). Depressive symptoms was assessed by the 15-items Geriatric Depression Scale (GDS) (Citation26), which has been validated for use in the local population in a prior study and showed a score of ≥ 5 to have high sensitivity and specificity in detecting major depression (Citation27,28). The presence of chronic illnesses was determined by self-reported medical history in the past 1 year, medication usage and procedure use: hypertension (self-report, blood pressure and antihypertensive use), diabetes mellitus (self-report, fasting blood sugar, and use of diabetic medication) and stroke (self-report of stroke or transient ischemic attack). Cardiac disease consisted of heart attack (self-report and ECG), atrial fibrillation (ECG), congestive heart failure (report and use of diuretics and use of vasodilator or cardiac glycoside).
Lifestyle data included current cigarette smoking (versus ex-smoker and non-smoker), alcohol intake (at least one drink in a week) and leisure time activities comprising ìfitness activities,î ìsocial activitiesî and ìproductive activities.î Participation in ìfitness activitiesî (ìwalking,î ìexercise routinesî and ìactive sportsî), ìsocial activitiesî (attending religious services, visiting cinemas, restaurants, and sports events; day or excursion trips; playing cards, games, bingos; participating in group activities, such as karaoke, line dancing; joining a senior citizen club activities), and ìproductive activitiesî (recreation and hobbies; preparing meals; shopping; paid or unpaid community work; other paid employment or business) were measured by the frequency (0 = never, 1 = sometimes, 3 = often) with which they engaged in these activities. Each respondent's level of participation in leisure time activities was measured by their respective summed scores.
Statistical analyses
The characteristics of the study population were first analyzed by descriptive analysis. The association between FEV1 percent predicted and each cognitive test was analyzed by multiple linear regression, controlling for age, sex, education, depressive symptoms, smoking, alcohol consumption, leisure activities score and history of hypertension, diabetes, stroke, cardiac disease, height and MMSE score (as appropriate). Analysis of covariance, controlling for the same covariates, was performed to investigate the relationship of categories of severity of pulmonary obstruction with cognitive performance. Adjusted mean score of each cognitive test was obtained by 3 different levels of pulmonary function and trend tests were performed for all the cognitive variables. Post-hoc comparisons were made if there was an overall difference among severity groups. Multiple comparisons were corrected by Bonferroni adjustment.
Finally, logistic regression was used to explore whether lower lung function was related to cognitive impairments and cognitive IADL disability. The regression coefficients (b) or odds ratios (ORs) associated with FEV1 percent predicted were all reported as magnitude related to every 10% change in FEV1 percent predicted. Two-sided P-values of < 0.05 were considered to be statistically significant. Analyses were conducted by SAS 9.2 (SAS Institute, Inc., Cary, NC).
Results
The total sample consisted of 2450 older adults. The mean age was 66 (±7.60 SD), 63% was female and 50% had a primary education and below. The mean FEV1 percent predicted was 0.98 (±0.22 SD) and approximately 10% had moderate or severe airway obstruction. The subsample data included 691 participants with a mean age of 65 (±6.72); 61% were female, close to half had a lower level of education and about 10% fell into the category of moderate to severe lung function ().
Table 1. demographical and clinical characteristics of population sample
shows the results of linear association between FEV1 percent predicted and cognitive performance from multiple regression analyses. FEV1 was positively associated with MMSE and executive function. Every 10% increase in FEV1 percent of predicted was related to 0.18 points of improvement in MMSE and 0.04 points in the score of executive function, other variables held constant. Predicted FEV1 explained about 0.8% variance in MMSE and about 0.9% in executive function.
Table 2. Multiple Regression Analyses of Associations with Neurocognitive Test Performance z-Scores per 10 percent increment of predicted of FEV1
The adjusted mean cognitive scores according to the categories of severity of airway obstruction are shown in . Subjects with pulmonary restriction or moderate to severe airway obstruction showed significantly lower MMSE score than the normal group. Scores on information processing speed for subjects with moderate to severe airway obstruction was significantly lower than the other 3 groups, with a significant linear trend across the 3 groups. We also observed significantly lower mean visual memory score for subjects with mild airway obstruction compared with normal group. The effect sizes were 0.015, 0.014 and 0.0350 for MMSE, visual memory and information processing speed. In contrast, we did not find any significant group differences for executive function and other cognitive domains performance.
Table 3. Adjusted mean (Standard Error) of MMSE and neurocognitive Z-scores stratified by spirometric abnormalities
The associations of pulmonary function with cognitive impairment and cognitive IADL disability are shown in . Higher FEV1 percent predicted, was significantly associated with lower risk of cognitive impairment (OR = 0.92, 95% CI: 0.87–0.98, P = 0.005) and cognitive IADL disability (OR = 0.86,95% CI:0.79–0.93, P < 0.001) independent of age, education and other confounders. Similarly, pulmonary restriction was associated with increased odds of cognitive impairment (OR = 1.98, 95% CI: 1.26-3.11, P = 0.003), and both pulmonary restriction (OR = 2.43, 95% CI: 1.31-4.53, P = 0.005) and moderate to severe airway obstruction (OR = 2.04, 95% CI: 1.11-3.74, P = 0.022) were associated with higher odds of cognitive IADL disability.
Table 4. Unadjusted and adjusted OR of association of pulmonary function with cognitive impairment and IADL impairment (n = 2450)
Discussion
Our data extends previous epidemiological studies supporting the association between pulmonary function with cognitive abilities. In this population of community-dwelling middle aged and older Chinese adults in Singapore, we found a linear positive relationship for pulmonary function with global cognitive and executive function. The estimated increment in MMSE score of 0.18 per 10% increment in FEV1% of predicted approximates to just under one year of age increase in this population of Asian older persons (Citation23). Also, given the small variances explained by FEV1, the contribution of pulmonary function to cognitive function appears to be modest at the population level.
Nevertheless, we found that better pulmonary function was also associated with a reduced risk of cognitive impairment assessed by MMSE and cognitive IADL disability. Participants with greater airway obstruction compared to those with no airway obstruction showed poorer cognitive performance with respect to global cognition, visual memory and information processing speed, controlling for age, gender, education and other correlates. Other cognitive domains including executive function did not appear to be affected by severity of airway obstruction. These findings are consistent with a previous study showing similar lack of a strong association for pulmonary function with all but a few cognitive abilities (Citation9).
Our findings of the positive associations between pulmonary function and visual memory and information processing speed are in line with previous reports showing similar cognitive effects of pulmonary function (Citation7–10). A notable finding in this study, however, is that pulmonary function was associated with design fluency measure of executive functioning ability, given the sparse data from previous studies on this cognitive domain effect in community-living older adults. Design fluency is generally assumed to assess executive functions (primarily planning, cognitive flexibility, and fluency in generating visual patterns) (Citation21,Citation29), although it has also been shown that generation of novel designs (from the first two trials) relied primarily on motor planning and the ability to generate novel motor actions, and the generation of unique designs while switching (third trial) relied primarily on visual scanning and perhaps visual-attentional resources (Citation30).
It is also worth noting that the everyday tasks in the Cognitive IADL scale comprise using telephone, taking medicine and managing money, items which require cognitive processing that include working and visual memory as well as executive function. This is the first time that the cognitive effect of pulmonary function has been shown to be accompanied by disability on cognitively demanding tasks of daily living.
There are biologically plausible explanations for the association between decreased pulmonary function and impaired cognitive ability. First, low respiratory and cognitive functions are both affected by lifestyle behaviors such as smoking and drinking (Citation31,32) as well as cardiovascular risk factors such as diabetes (Citation33) and hypertension (Citation34).
However, we observed in this study that the association between lung function and cognition persisted after controlling for these factors in the analysis. It has also been suggested that the link between low pulmonary function and atherosclerosis may be attributable to impaired fibrinolytic activity (Citation35) and chronic inflammation in the respiratory system (Citation36). Poor pulmonary function could increase vulnerability for small-vessel disease (Citation37) and ischemic damages to the brain by hypoxia. Studies suggest that hypoxia adversely affects the metabolism of central neurotransmitter, induced inflammatory responses, oxidative stress, ATP production and disrupts functional integrity of the blood-brain barrier (Citation15, Citation38). Recent studies show that lower pulmonary function was associated with the presence of white matter lesions (WMLs) and lacunar infarcts (Citation14) and their localization in fronto-striatal region is associated with executive dysfunction. Finally, there may be other unmeasured environmental or genetic risk factors that explain the link.
Our study has a number of limitations. First, this is a cross-sectional study hence it is difficult to draw firm causal inferences on temporal relationships. Mediating factors such as inflammatory biomarkers or chronic hypoxia were not measured in this study. Chronic hypoxia is a known mechanism underlying cognitive decline in COPD, and could possibly explain poor cognitive function among the study participants with moderate-to-severe obstruction. This could be evaluated in a 6-minute walk test, but regrettably this was not included in this study. Analyses of different cognitive tests were based on varying sample size due to incomplete testing and missing values. Finally, the examination of lung function was limited to only spirometry being performed without prior bronchodilatation to determine fixed airway obstruction characterizing COPD. This may contribute to some misclassification errors thus obscuring the cognitive effects of chronic airways obstruction.
Conclusions
In conclusion, our study suggests a measurable but modest cognitive effect of low pulmonary function including executive functioning that was associated with corresponding disability in instrumental daily living activities. The effect of low pulmonary function on cognitive and functional ability of community-living elderly should be confirmed in future longitudinal studies.
Declaration of Interest
The authors declare that there are no declarations of interest in relation to the current study. The authors are responsible for the writing and the content of this article. The study is supported by a research grant (No. 03/1/21/17/214) from the Biomedical Research Council, Agency for Science, Technology and Research (ASTAR).
Acknowledgments
The authors would like to thank the following voluntary welfare organizations for their support of the Singapore Longitudinal Ageing Studies: Geylang East Home for the Aged, Presbyterian Community Services, Thye Hua Kwan Moral Society (Moral Neighbourhood Links), Yuhua Neighbourhood Link, Henderson Senior Citizens’ Home, NTUC Eldercare Co-op Ltd, Thong Kheng Seniors Activity Centre (Queenstown Centre) and Redhill Moral Seniors Activity Centre.
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