| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ORIGINAL ARTICLES |
From the MRC National Survey of Health and Development, University College London, U.K. (M.R., R.H., D.K., M.W.); and the Department of Public Health Sciences, St. George’s Hospital Medical School, London, U.K. (D.S.).
Address correspondence and reprint requests to Marcus Richards, PhD, University College London, Department of Epidemiology & Public Health, 1–19 Torrington Place, London WC1E 6BT, U.K. E-mail: m.richards{at}ucl.ac.uk
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMETHODS AND MATERIALSRESULTSDISCUSSIONNOTESREFERENCES |
|---|
Methods: Multiple regression was used to test associations between FEV1 and cognitive function in 1778 men and women in the MRC National Survey of Health and Development, also known as the British 1946 birth cohort. Analyses were adjusted for sex, body size (birth weight, adult height, weight, and chest circumference), socioeconomic status, lifetime smoking, and a range of health indicators, including early respiratory vulnerability (infant lower respiratory infection, childhood asthma, and exposure to atmospheric pollution).
Results: FEV1 at 43 years was associated with slower psychomotor speed (peg placement) at the same age and with slower decline in psychomotor speed (letter search speed) from 43 to 53 years, independently of the previously mentioned potential confounders. These independent associations were not observed, however, for adult verbal ability, verbal memory, or rate of decline in memory, which were significantly explained by socioeconomic status and adolescent cognitive ability. In a subsequent analysis, adolescent cognition was positively associated with FEV1, although not with rate of decline in FEV1 from 43 to 53 years, again independently of the previously mentioned confounders.
Conclusions: Cognitive function and FEV1 are positively associated across the life course. One possible explanation lies in the parallel action of endocrine, autonomic, and motor control systems on respiration and higher mental function. Because respiration and mental function are both associated with functional capacity and survival, this is a matter of potential clinical significance.
Key Words: lung function • cognitive function • birth cohort
Abbreviations: AH4 = Alice Heim group abilities test; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume within 1 second; FVC = forced vital capacity; NSHD = National Survey of Health and Development; NART = National Adult Reading Test; SES = socioeconomic status.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODS AND MATERIALSRESULTSDISCUSSIONNOTESREFERENCES |
|---|
In terms of underlying mechanisms, the most widely held view is that impaired lung function causes changes in the central nervous system (CNS) through possible processes such as vascular disease resulting from inflammation, impaired fibrinolytic activity, oxidative stress or cardiovascular risk factors (see 15), or hypoxia-induced changes in neurotransmitter metabolism (16). Such CNS changes then lead to lower cognitive function. However, given that respiratory control requires the operation of brain structures across many levels of the neuraxis (17), it may be that cognitive function is a marker of the general integrity of neurorespiratory regulation. If so, the association between respiration and cognition may be evident at an earlier stage of the life course.
The British 1946 birth cohort study has measured pulmonary function in midlife before lung disease has had a major impact on survival. We investigated the association between lung function and cognition at 43 years, and between lung function at this age and change in cognitive function from 43 to 53 years, controlling for a range of sociodemographic, socioeconomic, and health-related indicators. We then investigated the association between childhood cognition and adult lung function and change.
|
METHODS AND MATERIALS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODS AND MATERIALSRESULTSDISCUSSIONNOTESREFERENCES |
|---|
Lung Function
Lung function was represented by forced expiratory volume in 1 second (FEV1) measured at 43 years and 53 years using a Micro Medical Micro Plus spirometer, administered by a trained nurse. On both occasions, participants were asked to stand, fill their lungs to capacity, make an airtight seal around the mouthpiece with their lips, then blow as hard and fast as possible until their lungs were empty. Participants did not wear a noseclip. The nurse first demonstrated the technique and then provided verbal encouragement during the trials. Three trials were given at 43 years, and 2 trials were given at 53 years. The higher value of the first 2 trials, and of either trial, respectively, was used for analysis. When the survey member’s spirometer technique at 53 years was rated as unsatisfactory by the nurse, values for that trial were classified as missing data. Nine survey members were excluded from the analysis because their technique was unsatisfactory on both trials. These nurse ratings were not undertaken at 43 years. Variation in FEV1 across both trials was within 5% for 77.5% of the sample at 43 years and 79.6% of the sample at 53 years.
Adult Cognitive Measures
At 43 years, they were given a timed peg placement test (overall mean of 3 trials for each hand subjected to a log transformation to improve distribution), and at 43 and 53 years, they were given repeat tests of memory (a 3-trial 15-item word list), and speed and concentration (timed letter search). A different word list was given to each half of the cohort at 43 years, and then these lists were reversed at 53 years. Target letters were in different positions on the page at 43 and 53 years. At age 53, they also took the National Adult Reading Test (NART) (20), a test of verbal ability requiring the pronunciation of 50 irregular words of increasing difficulty. All cognitive measures were administered after appropriate training to the nurses.
Potential Confounding Variables
Body size is a potential confounder because birth weight is associated with ventilatory function (21), because FEV1 increases with height, and because pre- and postnatal growth is associated with cognitive function (22,23). The following parameters were used: birth weight, adult leg length, trunk length, expanded chest circumference, and weight current to FEV1 at 43 years. Adult standing height was measured at 53 years to the nearest 0.5 cm using a portable stadiometer, as was sitting height (to represent trunk length). Leg length was calculated as the difference between sitting and standing height. Expanded chest circumference was also measured at 53 years in men at nipple level and in women immediately below the breasts.
Socioeconomic status (SES) was represented by father’s social class, mother’s education, material home conditions, own educational attainment, and own current or last occupational social class at 43 years. An aggregate variable representing material home conditions at age 4 years comprised ratings by a health visitor of age, cleanliness, and state of repair of the dwelling; number of people per room; and cleanliness and condition of clothing and shoes of the survey member. This total score was then categorized into very good, good, modest, or poor (24). For own educational attainment, the highest educational qualifications and their training equivalents attained by 26 years were classified as none, vocational only, ordinary secondary (O levels), advanced secondary (A levels), or degree level or equivalent. Social class was classified as professional, managerial, intermediate, skilled manual, semiskilled manual, or unskilled, according to the Registrar General.
Smoking impairs FEV1 and is associated with cognitive decline (25). Information on daily cigarette consumption was obtained at ages 20, 25, 31, 36, 43, and 53 years. A measure of lifetime smoking to 43 years was calculated by multiplying pack-years at each age by the number of years to the next age (e.g., smoking exposure from 25–31 years was calculated as pack-years at 25 multiplied by 6), and then totalling and averaging these products. To include adolescent smoking, pack-years at 20 years was multiplied back to 16 years.
Other health-related measures at 43 years such as physical exercise, which is protective of cognitive decline (26), was classified as 0, 1 to 4, or 5+ sporting or recreational activities per month based on an equivalent scheme for activities at 36 years (27). Resting pulse and systolic and diastolic blood pressure were measured by a research nurse. Significant respiratory problems were classified by self-reports of any of the following: a wheezy or whistling chest most days or nights, usually bringing up phlegm or coughing in the morning or during the day or night in winter for at least 3 months each year, or any chest illness (e.g., bronchitis, pneumonia) that required sickness absence of a week or more. Affective state was measured by the Psychiatric Symptom Frequency (PSF) scale (28).
Information on lower respiratory infection in infancy, which is a risk factor for adult respiratory problems (29,30), was provided by the respondents’ mothers. A small number of survey members (n = 58) had also been noted as having asthma by a school doctor at 6, 11, or 15 years. Because this cohort was born 10 years before the Clean Air Act of 1956, exposure to air pollution from incomplete coal combustion from birth to 9 years, estimated from validated measures (31), was also used as a potential confounder.
To investigate a possible neurodevelopmental pathway to lung function, the effect of adjusting for cognitive ability at 15 years was examined. At this age, children took the Heim AH4 test (32), the Watts-Vernon Reading Test (33), and a mathematics test. The AH4 is a 130-item ability test, with verbal items (analogies, comprehension, and numerical reasoning) and nonverbal items (matching, spatial analysis, and nonverbal reasoning) summed to yield a general ability score. The Watts-Vernon is a test of reading comprehension, requiring selection of appropriate words to complete 35 sentences. The mathematics test consisted of 47 items, requiring the use of arithmetic, geometry, trigonometry, and algebra. Concerning reliability of these tests, Pidgeon (33) quoted a figure of 0.92 for test–retest consistency of the total AH4 score with an interval of 1 month, a figure of 0.89 for reliability of the Watts-Vernon reading test as calculated from the Kuder-Richardson Formula 20 test, and noted a similar figure for test–retest analysis.
Scores for these three tests were summed to obtain an overall score representing general cognitive ability. This score was normally distributed within the present study sample.
Statistical Analysis
The association between FEV1 at 43 and midlife cognitive function was tested using memory, search speed, and peg placement speed at 43 years, and the NART at 53 years as outcomes. Conditional models of change were used to investigate the association between FEV1 at 43 and change in memory and search speed from 43 to 53 years, adjusting the memory and search speed scores at 53 years for their corresponding scores at 43 years. These analyses were performed in stages, controlling for sex and body size (model 1), then SES (model 2), then lifetime smoking (model 3), and then cognition at 15 years (model 4). We then tested the association between cognitive ability at 15 years and FEV1 at 43 years, and, also using conditional analysis of change, rate of FEV1 decline from 43 to 53 years, similarly adjusting for covariates in stages, according to models 1 to 4.
For all analyses, FEV1, the age 15 cognitive ability score, lifetime smoking, and all body size parameters were entered as continuous variables, whereas education and social class were entered as categorical variables.
Finally, all stage 4 models were adjusted for each remaining health indicator in turn, i.e., physical exercise, pulse, blood pressure, adult lung disease, affective state (PSF), infant lower respiratory infection, childhood asthma, and atmospheric pollution.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODS AND MATERIALSRESULTSDISCUSSIONNOTESREFERENCES |
|---|
Forced Expiratory Volume in 1 Second and Midlife Cognition
Tables 1 to 3 show regression coefficients and 95% confidence intervals representing mean increase in peg placement time at 43 years and verbal ability (NART) at 53 years, and mean difference (change) in memory and search speed for given memory and search speed scores at 43 years, per unit increase in FEV1 at 43 years, in which positive coefficients represent slower decline. These associations were adjusted for sex and body size (model 1), then SES (model 2), then lifetime smoking (model 3), and then cognitive ability at 15 years (model 4).
|
|
|
Although FEV1 was strongly associated with the NART at 53 years with sex- and body size-adjusted (model 1), the strength of this association was greatly reduced after controlling for SES. The coefficient was essentially unchanged by subsequent control for lifetime smoking. Indeed, when smoking was added to model 1 without adjustment for SES, FEV1 was still strongly associated with the NART (p < .001). However, the association was further reduced by control for adolescent cognitive ability (model 4), after which it was no longer significant at the 5% level. Adding adolescent cognitive ability to the model substantially reduced the strength of association between SES and the NART (not shown), and therefore accounted for a significant proportion of its effect.
A similar pattern to that for the NART was observed for verbal memory at 43 years. The association was positive and significant with only sex and body size in the model (Table 2, model 1), but was also strongly reduced after controlling for SES and lifetime smoking. Smoking added to model 1 by itself reduced the association, although the effect of FEV1 remained highly significant (p < .001). Again, the association was further reduced by controlling for adolescent cognitive ability (model 4), after which it was no longer significant at the 5% level. Higher FEV1 was weakly associated with slower rate of decline in memory from 43 to 53 years, although this effect was reduced to nonsignificance after controlling for SES and smoking (p = .24 for smoking added to model 1 alone), and almost completely attenuated after further control for adolescent cognition. Again, age 15 cognition explained to a significant extent the association between SES and verbal memory, and, indeed, reduced the associations between FEV1 and memory to nonsignificance when entered without SES or smoking (p = .08 and .50 for memory at 43 years and change in memory from 43 to 53 years, respectively).
Whereas FEV1 was not associated with search speed at 43 years (Table 3), higher FEV1 was associated with slower rate of decline from 43 to 53 years in this measure, even after adjustment for sex, body size, SES, smoking, and adolescent cognition (models 2–4). The strength of the association for search speed change in model 4 was not significantly altered by further control for peg placement time (p = .01), suggesting that FEV1 is associated with the cognitive (e.g., attentional) component of the visual search task, as well as with the motor speed component.
None of these model 4 associations were significantly altered by further adjustment, in turn, for infant lower respiratory infection, childhood asthma, early exposure to atmospheric pollution, adult lung disease, engagement in physical exercise, resting pulse, systolic or diastolic blood pressure, or affective state (not shown).
Cognitive Ability at 15 Years and Midlife Forced Expiratory Volume in 1 Second
Because of the significant effect on most of the previously mentioned associations of adjusting for adolescent cognitive ability, the association between adolescent cognitive ability and midlife FEV1 was itself investigated. Table 4 shows regression coefficients and 95% confidence intervals representing mean difference in FEV1 at 43 years per unit increase in ability at 15 years, progressively adjusting for sex and body size, SES, and smoking.
|
It can be seen that ability at 15 years was positively associated with FEV1 after adjusting for sex and body size (model 1). The strength of this association was reduced after adjusting for SES and lifetime smoking, although it remained significant at the 5% level throughout. Smoking added to model 1 alone reduced the association (p < .001), although not by as much as SES. When the cognitive ability score was divided into fifths, the difference in mean FEV1 between the lower and upper fifths, adjusted for all covariates, was 0.49 L, in which mean overall FEV1 was 2.95 L. This is illustrated in Figure 1.
|
Table 5 shows regression coefficients representing the association between cognitive ability at 15 years and rate of decline in FEV1 from 43 to 53 years, in which positive associations represent slower decline. Higher ability at 15 years was associated with slower decline in FEV1 after adjusting for sex and body size (model 1). This association was reduced to nonsignificance by control for SES (model 2), although not when smoking was entered without SES (p = .01).
|
Like with FEV1 and adult cognition, none of these model 3 associations for childhood ability were significantly altered by further adjustment, in turn, for infant lower respiratory infection, childhood asthma, early exposure to atmospheric pollution, adult lung disease, engagement in physical exercise, resting pulse, systolic or diastolic blood pressure, or affective state (not shown).
When FEV1/FVC (forced vital capacity) ratio was substituted for FEV1, this adjusted ratio was significantly associated with peg placement time (p = .006) and rate of decline in search speed (p = .01). However, associations between childhood IQ and this ratio at 43 years, and between change in this ratio from 43 to 53 years were not significant at the 5% level. This may be because FVC is less accurately measured by the Micro Medical spirometer than FEV1.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODS AND MATERIALSRESULTSDISCUSSIONNOTESREFERENCES |
|---|
In a further series of analyses, we also found that cognitive ability at 15 years was positively associated with FEV1 at 43 years, also independently of the previously mentioned potential confounders, although not with change in FEV1 from 43 to 53 years, which was largely explained by SES. This possibly implies a neurodevelopmental pathway that predicts growth but not decline in lung function.
Principal strengths of this study are the availability of cognitive measures across the life course, repeated measures of FEV1 in midlife, and the range of potential confounders noted here. Two limitations, however, should be noted. First, there was a disproportionate loss to follow up of those with lower cognitive ability, a familiar problem in studies of cognitive aging. This bias limits generalizability of our findings, and may have led to underestimation of the strength of association between cognition and FEV1. Second, although we were able to control for a wide range of confounders, we were not, at this time, able to adjust for nutrients of potential importance for cognition and for lung function such as antioxidant vitamins (34). Such data will be available for future analysis.
With these strengths and weaknesses in mind, what might underlie the association between cognitive function and lung function? There are several psychosocial factors of potential significance, including the role of motivation and compliance, although the association was not confounded by affective state. It also seems unlikely that it was explained by varying ability to follow instructions. This might have resulted in an inverse J-shaped curve, with markedly poorer ventilatory function in those of lowest ability, but is unlikely to have produced the observed linear trend between cognition at 15 and adult lung function.
At the biologic level, it is sometimes assumed that changes in lung function alter cerebral oxygenation. This is plausible for those with severe lung disease such as hypoxemic COPD, although controlling for self-reported lung disease in this study did not significantly alter our results. In healthy individuals, however, homeostatic mechanisms to maintain stable cerebral oxygen levels are highly effective. For example, PO2 and brain blood flow remain constant during exercise even in the face of massive increase in cardiac output (35,36). There is a strong linkage between cerebral blood flow and neurometabolism that is regionally precise. For example, complex cognitive activity produces an increase in flow to several brain regions, but this involves redistribution, whereas whole-brain metabolic rate and blood flow remain constant (37). A different possibility is that low FEV1 is a risk factor for cerebral infarction and white matter lesions, which in turn are associated with cognitive decline. Although there is evidence for both of these propositions (15,38,39), this evidence comes from studies of older people, and controlling for blood pressure (hypertension being a risk factor for cerebral vascular disease (40)) did not alter the association between FEV1 and cognition in this middle-aged sample.
An intriguing clue as to the nature of the association between lung function and cognition is that we found cognitive ability in adolescence to be specifically associated with FEV1, possibly reflecting a neurodevelopmental pathway to adult lung function. Given that respiratory control requires the operation of brain structures across many levels of the neuraxis (17), it may be that cognitive function is a marker of the general integrity of the neurorespiratory system. From this perspective, lung and cognition function, rather than having a causal relationship, may simply covary across the life course according to common regulatory processes. This echoes, from a developmental perspective, the common-cause theory of aging (41). Unfortunately, ventilatory function was not measured in childhood, and so we cannot confirm whether the association between FEV1 and cognition was already present at this stage of the life course. This seems a reasonable possibility, however, in view of evidence that ventilatory and cognitive function both track across the life course (42,43).
In terms of normal function, there are, in fact, numerous candidates for such common processes, i.e., biochemical aspects of respiratory control that are also involved in higher mental function. These include the hormones estrogen and thyroid, all of the major monoamines (acetylcholine, dopamine, noradrenaline, and serotonin), the amino acid GABA, and a range of neuropeptides (44). A further possibility concerns the role of the hypothalamic–pituitary–adrenal (HPA) axis. In rats, prenatal dexamethasone affects the development of many organ systems, including the lung (45), and in humans, cortisol, which in excess is capable of damaging neural structures important for cognition (46), was found to be negatively associated with lung function in the MacArthur Studies of Healthy Aging (9). Of possible relevance in this context, rate of decline in psychomotor speed, which was slower in the present study with increasing FEV1, was exacerbated by early emotional adversity in this cohort (24); indeed, the outstanding long-term cognitive effect of this exposure. Glucocorticoids also regulate insulin-like growth factors during development (47,48) that target areas of the brain important for cognition as well as determining physical growth (49). With the caveat that the association between lung function and cognition in our study was not explained by body size, our finding of an association between cognition during the developmental years and lung function is consistent with the early effects of these control systems. These matters deserve further investigation.
|
NOTES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODS AND MATERIALSRESULTSDISCUSSIONNOTESREFERENCES |
|---|
The National Survey of Health and Development is funded by the Medical Research Council. Data collection at 53 years was carried out by the National Centre for Social Research.
DOI:10.1097/01.psy.0000170337.51848.68
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODS AND MATERIALSRESULTSDISCUSSIONNOTESREFERENCES |
|---|
This article has been cited by other articles:
 |
|
 |
|
  E. J. Giltay, A. Nissinen, S. Giampaoli, F. G. Zitman, and D. Kromhout Low Respiratory Function Increases the Risk of Depressive Symptoms in Later Life in Men Psychosom Med, January 1, 2010; 72(1): 53 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Hung, J. P. Wisnivesky, A. L. Siu, and J. S. Ross Cognitive Decline among Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., July 15, 2009; 180(2): 134 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Clennell, D Kuh, J M Guralnik, K V Patel, and G D Mishra Characterisation of smoking behaviour across the life course and its impact on decline in lung function and all-cause mortality: evidence from a British birth cohort J Epidemiol Community Health, December 1, 2008; 62(12): 1051 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Orfei, D P Strachan, A R Rudnicka, and M E J Wadsworth Early influences on adult lung function in two national British cohorts Arch. Dis. Child., July 1, 2008; 93(7): 570 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Suglia, R. O. Wright, J. Schwartz, and R. J. Wright Association Between Lung Function and Cognition Among Children in a Prospective Birth Cohort Study Psychosom Med, April 1, 2008; 70(3): 356 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Deary, L. J. Whalley, G. D. Batty, and J. M. Starr Physical fitness and lifetime cognitive change. Neurology, October 10, 2006; 67(7): 1195 - 1200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wadsworth, D. Kuh, M. Richards, and R. Hardy Cohort Profile: The 1946 National Birth Cohort (MRC National Survey of Health and Development) Int. J. Epidemiol., February 1, 2006; 35(1): 49 - 54. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
