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Ventilatory Capacity and Risk for Dementia

^a Department of Psychiatry, Free University of Berlin, Germany
^b Geriatric Research Group, Department of Medicine, Virchow-Klinikum, Humboldt University, Berlin, Germany
^c Max Bürger Zentrum for Geriatric Psychiatry, Berlin, Germany
^d King's College London, Department of Public Health Sciences, United Kingdom
^e Department of Psychiatry and Psychotherapy, Ernst-Moritz-Arndt-University, Greifswald, Stralsund, Germany

Rainer T. Schaub, Department of Psychiatry and Psychotherapy, Ernst-Moritz-Arndt-University Greifswald, Rostocker Chaussee 70, 18437 Stralsund, Germany E-mail: schaub{at}mail.uni-greifswald.de.

William B. Ershler, MD

	Abstract

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Background.

Previous studies have found a relationship between single indicators of ventilatory capacity and measures of cognitive function, but have not addressed dementia specifically. This study examined the relationship between different indicators of ventilatory capacity and dementia, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, controlling for important confounding factors.

Methods.

Cross-sectional data on participants (n = 437) of the Berlin Aging Study (BASE), which are representative of former West Berlin's living population aged 70 years and older, were analyzed. Ventilatory capacity was measured by spirometry as peak expiratory flow rate (PEF-R), forced expiratory volume in 1 second (FEV-1), maximal expiratory flow at 50% of forced vital capacity (MEF_50%FVC), and maximal expiratory flow at 25% of forced vital capacity (MEF_25%FVC). Odds ratios (OR) for dementia associated with ventilatory capacity were obtained by logistic regression, adjusting for age, gender, education, ApoE4 status, chronic obstructive pulmonary disease, smoking, heart failure, visual and auditory functioning, grip strength, and former physical activity.

Results.

Separate analyses for PEF-R, FEV-1, MEF_50%FVC, and MEF_25%FVC revealed significantly increased odds for dementia among subjects in the lowest compared with the best functioning group in ventilatory testing. The OR associated with PEF-R 2 l/s was found to be 20.4 (confidence interval [CI] 5.1–82.7). For FEV-1, MEF_50%FVC, and MEF_25%FVC, ORs of 7.5 (CI 2.1–27.9), 4.3 (CI 1.5–12.5), and 4.7 (CI 1.3–17) were obtained, respectively.

Conclusions.

Ventilatory capacity, measured by spirometry in a representative sample of very elderly people, is cross-sectionally related to dementia. Taking evidence from longitudinal studies into account, this result suggests that decreased respiratory function may increase the risk for dementia, independent from already known risk factors.

IN addition to genetic risk factors for dementia (i.e., for late onset type of Alzheimer's disease [AD]) ⁽¹⁾, several presumably nongenetic factors have been suggested ⁽²⁾.

Three studies have reported a relationship between respiratory functioning and cognitive decline in large, population-based samples of elderly people. All three provide some evidence for a causal relationship, because of analytical methods used ⁽³⁾ or longitudinal design ⁽⁴⁾⁽⁵⁾. None of these studies addressed dementia directly, and all three examined single measures of ventilatory capacity, which are strongly effort dependent and thus may have been biased by factors such as cooperation.

The present study had the following objectives: (i) to investigate if findings on the relationship of cognitive function and effort-dependent spirometric measures also extend to the clinical diagnosis of dementia; (ii) to examine whether dementia is also associated with effort-independent spirometric measures; and (iii) to investigate if the association between dementia and spirometric measures is independent from possibly confounding factors such as frailty or ApoE genotype.

We analyzed the cross-sectional association between respiratory function, measured by four spirometric indices, and dementia, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R). Spirometric indices used in our study reflect the function of different parts of the respiratory system and differ in their degree of effort dependence. Hence, we were able to examine whether primary intrapulmonary, effort-independent (i.e., alveolar), or extrapulmonary, effort-dependent (i.e., bronchial) factors relate to dementia. The design of the Berlin Aging Study (BASE) ⁽⁶⁾ allowed to control for known important risk factors for dementia, such as age, gender, education, smoking, or ApoE genotype. Measures of sensory functioning and frailty, reflecting biological more than chronological age, were also included, because parameters of spirometric performance also depend on aging-related, noncognitive functional changes.

	Methods

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Subjects
The BASE sample is designed to be representative of the western part of the city of Berlin and to oversample the very elderly and the male populations (described in ⁽⁷⁾). In brief, it is a probability sample of community-dwelling as well as institutionalized individuals (N = 516), aged 70–103 years, and consists of equal numbers of men and women in six age brackets (70–74, 75–79, 80–84, 85–89, 90–94, and 95+ years). Of the participants, 86.4% were community dwelling, and 13.6% resided in institutions (sheltered housing, residential homes, nursing homes, hospitals for the chronically ill).

Examination Procedures
Psychiatric examination with the Geriatric Mental State-A/History and Etiology Schedule ⁽⁸⁾ was performed by study psychiatrists at the subject's place of living. Psychiatric diagnoses were made by study psychiatrists, who liaised with the geriatric unit according to defined rules ⁽⁹⁾. If necessary, close informants were interviewed by the psychiatrist. Data concerning neuropsychological and sensory functions were obtained independently by trained research assistants, but not used for diagnosis. Psychiatric diagnoses, therefore, were based on psychiatric and physical examination and eventually informants' interview data. Diagnoses of dementia were made according to the DSM-III-R, although criteria for Alzheimer's disease according to the National Institute of Neurological Diseases and Related Disorders Association ⁽¹⁰⁾ could not be applied because of the age range of subjects, extending far beyond 90 years. The Hachinsky score ⁽¹¹⁾ was used instead to identify subjects with a probable vascular origin of dementia. During examination, the geriatrician was not aware of the psychiatrists' diagnoses and vice versa.

Visual function was measured by reading tables for near and far distances, expressed in Snellen decimals. Hearing was tested using pure tone threshold audiometry (Audio Bosch ST 20, Bosch, Germany). A mean threshold value was calculated for speech (0.5 to 2 kHz) frequencies.

Grip strength was used as an indicator of physical strength, measured in kilograms (kg) by a Dyna-Chip dynamometer (Mechatronic, Hamm, Germany). For thoracic elasticity, the difference in thoracic circumference between maximum inspiration and expiration was determined.

Information concerning lifestyle factors as well as education was obtained from the participant or a caregiver (i.e., former and/or current smoking or physical activities). Former physical activities and smoking history were thought to confound the relation between spirometric performance and dementia and were therefore included in the models.

Indicators of somatic health status were presence of congestive heart failure and chronic obstructive pulmonary disease (COPD), both diagnosed by a geriatrician according to the International Classification of Diseases (ICD-9).

Routine laboratory tests, including thyroid function, were performed to rule out other causes of dementia. ApoE4-allele status was determined by restriction isotyping following DNA amplification ⁽¹²⁾.

Spirometric examination was performed during standardized geriatric assessment shortly before or after psychiatric examination by study geriatricians. A portable spirometer (Cardiovit ATG, Schiller, Switzerland) was used. Spirometric evaluation was performed in the sitting position. All participants underwent three consecutive spirometric trials, and the results of the best were used in the present analyses. Trials were repeated, when American Thoracic Society (ATS) standards ⁽¹³⁾ were not met. If spirometric tracings did not meet end-of-test criteria after repeated procedures, the best trial was selected, if the overall quality was acceptable, as recommended elsewhere ⁽¹⁴⁾. In addition, the subject's ability to cooperate in the spirometric examination was rated by the geriatrician.

We used the following spirometric indicators: forced expiratory volume in 1 s (FEV-1), which represents the best reproducible and reliable integral measure for the whole respiratory system; peak expiratory flow rate (PEF-R), which reflects the most effort-dependent part of respiratory function, also depending on height, thoracic volume, and muscular power in persons with normal bronchi and alveoli ⁽¹⁵⁾; and maximal expiratory flow at 50% of forced vital capacity (MEF_50%FVC) and 25% of forced vital capacity (MEF_25%FVC). These indicators reflect more closely the function of airways around a diameter of 3 mm, and are virtually effort independent ^(15)(16).

Data Analysis
Descriptive statistics are given as means and standard deviations (SD) or as frequencies and percent rates. Continuous variables were compared with t tests for unpaired groups, and categorical data were analyzed by crosstabulation based on ² distributions or Fisher's exact test. The relationship between spirometric indices and dementia was analyzed by standard logistic regression models. Likelihood ratio tests were used for model comparisons.

Modeling proceeded in two steps: first, age, gender, risk factors, and potential confounders were analyzed; in a second step, each indicator of ventilatory capacity was added in a separate regression model, resulting in five models (confounders only, PEF-R and confounders, FEV-1 and confounders, etc.). Because of intercorrelation of spirometric measures, separate regression models for each spirometric variable were used. Interaction terms for measures of ventilatory capacity with other covariates were also tested, but no significant improvement was observed; thus, results are not reported.

For all models, we used a set of continuous variables (age, maximum grip strength, visual and auditory function, height, and difference in thoracic circumference) and a set of binary variables (coded 0/1 for gender [male/female], educational level [elementary school, no formal occupational training/other, higher levels], current and/or former smoking [no/yes], presence of chronic obstructive pulmonary disease [COPD] or congestive heart failure [not present/present], former sports activities [none at all/any kind of leisure or professional sports], geriatricians' rating of cooperation [good, moderate/poor] and ApoE4 status [no 4 allele/one or two 4 alleles]).

Intervals for spirometric performance were derived from quartiles (FEV-1, PEF-R, and MEF_50%FVC), or terciles (MEF_25%FVC), resulting in approximately equal-sized groups. Indicator coding was used, defining the best functioning group as the reference category.

Reliable spirometric data were obtained from 490 subjects. Fifty-three subjects were excluded because of missing values in covariates, resulting in a sample size of 437 subjects eligible for analyses of effort-independent measures (MEF_50%FVC and MEF_25%FVC). When ATS standards were met, but cooperation was rated "poor" for other reasons, we excluded those subjects (n = 14) from analyses for effort-dependent measures (FEV-1, PEF-R), resulting in a sample size of 423. Excluded subjects were older and more likely to suffer from impaired sensory functioning. They were more often demented and institutionalized, predominantly women, less educated, and had lower spirometric performance. In summary, excluded subjects were more likely to be in the lowest level of functioning for most domains.

	Results

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Eligible subjects had a mean age of 84.3 (SD = 8.4) years, 235 (53.8%) were men. A diagnosis of dementia was made for 79 subjects (18.1%; see Table 1 ). Those with mild dementia according to the DSM-III-R had a mean Mini-Mental State Examination (MMSE) score of 22.7 (SD = 3.6); those with moderate dementia, 19.9 (SD = 4.3); and those with severe dementia, 16.2 (SD = 4.5). Of 79 demented subjects, seven (8.9%) had a Hachinsky score above 6, indicating primary vascular origin, whereas 17 (21.6%) scored above 4, indicating mixed and degenerative dementia. For the main part of analyses, cases with different etiologies were pooled because of sample size considerations.

View larger version (42K): [in this window] [in a new window]   Figure 1. Relation of peak expiratory flow rate (PEF-R) to dementia. On the abscissa PEF-R intervals (l/s) are used for grouping. The ordinate represents the according percent of demented and nondemented subjects. Numbers above bars represent the exact percent of demented and nondemented subjects, respectively.

With regard to ApoE4, we found odds ratios (ORs) of about 2.8, consistent with results from other population-based series.

When the seven dementia cases with a Hachinsky score >6 were excluded from the analysis, results remained essentially unchanged. Exclusion of 17 cases with a score >4 revealed no changes in ORs, but widened confidence intervals (CIs) included 1 because of the smaller number of cases. Exclusion of subjects with MMSE scores <17 (n = 20) slightly decreased ORs for all spirometric variables and also widened CIs, but for FEV-1 virtually the same figures were found (ORs 4.9, 5.7, and 6.4, respectively; no CI included 1). For PEF-R, ORs changed to 7.5, 9.1, and 14.0; no CI including 1. For MEF_50%FVC and MEF_25%FVC, nearly the same figures as in Table 3 were obtained.

Because exclusion of cases with any missing covariate value substantially decreased the sample size and thus might lead to a conservative selection bias, we repeated the main analyses with mean substitution for missing values. However, the ORs obtained in these analyses (including all 516 subjects) were essentially the same compared with those obtained without mean substitution (including the 437 or 423 subjects).

	Discussion

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In this population-based sample of elderly subjects, we found a strong relationship between measures of ventilatory capacity and dementia. Since CIs were overlapping, we cannot prove a dose-response relationship, nevertheless the odds for dementia increased with decreasing ventilatory capacity.

Some limitations of this study need further consideration: Of the subjects, 15.4% were excluded because of missing values. This probably caused a positive selection bias with the exclusion of 28.5% of demented and 12% of nondemented subjects. Because dementia was the targeted condition, this bias caused under- rather than overestimation of the analyzed relations and thus may be acceptable. Furthermore, a mean substitution procedure revealed no substantial differences from reported results.

A major advantage of the BASE is its multidisciplinary approach, with independent examination of all participants by two physicians. This allowed a comprehensive examination and adjustment for confounding factors that have not been controlled in other studies.

Because this analysis is cross sectional, dependence of spirometric testing on subjects' ability to cooperate and to understand instructions is critical. It has been shown recently ⁽¹⁷⁾ that spirometric indicators like FEV-1 or FVC in elderly persons with severe cognitive disturbance might not be reliable, raising concerns about the validity of spirometric tests in this population. On the other hand, there is evidence ^(14)(18) that in the vast majority of elderly persons acceptable spirometry tracings can be obtained, even in cognitively impaired subjects. Restricting analyses to participants with less pronounced cognitive impairment, or good and moderate cooperativeness, did not change results substantially.

Concerning motivation and effort, we had no indication that there was notable noncompliance in subjects taking part in the study, which consisted of at least 14 sessions. Taken together, it is unlikely that observed associations can be attributed to measurement bias alone.

Therefore, other explanations, not mutually exclusive, have to be considered: first, dementia and reduced ventilatory capacity both might be a common consequence of another condition; second, the association might be a systemic or functional consequence of dementia itself; and third, a cause-effect relationship can be assumed.

Concerning the first explanation, age might be the most important confounding factor for the association between dementia and reduced ventilatory capacity. However, the importance of age can only be evaluated by its functional consequences. We therefore controlled for chronological age and additionally for various confounding factors reflecting biological age. When evaluating the model with confounders only (Model 0), it appeared that chronological age, the most important univariate predictor of dementia, did not improve the model, whereas covariates, reflecting frailty or impaired sensory function, were associated with dementia. Hence, the observed relation between dementia and ventilatory capacity is probably not explained by chronological age alone nor by important age-associated functional changes. Nevertheless, this does not rule out other, possibly specific (i.e., genetic, endocrine), but as yet unidentified causes.

The second explanation (i.e., reduced ventilatory capacity as a consequence of dementia or dementia-related processes) implies that dementia not only impairs cognitive functions, but affects other physiological systems as well. Evidence from several studies suggests that dementia, predominantly of the Alzheimer's type, also impairs autonomic nervous and endocrine function ^(19)(20) as well as blood pressure ⁽²¹⁾. Thus, at least for AD, dementia-associated impairments may also extend to respiratory or pulmonary function. However, analyses were adjusted for physical strength and elasticity of the thoracic cage; therefore, a rather selective impairment in thoracic or phrenic muscles, or impaired function of airways with larger caliber, would have to be assumed. Clarification of this issue requires analysis of data from subjects with different types of dementia (i.e., Lew body dementia or vascular dementia). In our sample, exclusion of cases with presumed vascular origin of dementia did not change ORs substantially, which suggests that the relation holds, at least for primary degenerative types of dementia. Taken together, we cannot completely rule out the second explanation, that impaired ventilatory capacity might be a consequence of dementia.

The third explanation is that of a causal effect of ventilatory capacity on dementia. We cannot determine the direction in time of this relation because of our study's cross-sectional design. But, taking MacArthur's studies into consideration ⁽⁴⁾, which showed that PEF-R predicted the degree of cognitive decline over 2 years in a sample of originally unimpaired, healthy elderly persons, there is evidence that respiratory function can increase the risk for cognitive decline. It seems reasonable then to assume that this cause-effect-like relation is not only valid for a decline in cognitive function, but also for the development of dementia. Results from the Honolulu Heart Study support this interpretation, in which over 3,000 men of Japanese origin underwent spirometric testing and were examined at least 23 years later. The authors ⁽⁵⁾ do not address dementia but cognitive function, although subsequent reports from the Honolulu-Asia Aging Study ⁽²²⁾ show that a significant part of their sample had received this diagnosis. If one accepts the argument that cognitive and pulmonary function are not associated throughout the entire life, then both studies demonstrate that impaired ventilatory capacity increases the risk for impaired cognitive function in later life.

We have observed, in addition, that dementia shows a close association to decreased ventilatory capacity, and that this association is strongest for PEF-R, but also holds for measures reflecting pulmonary function more directly (MEF_50%FVC, MEF_25%FVC), that is, resistance of small airways of the intrapulmonal part of the respiratory system. For those thought to be rather effort independent, the association was weakest but nevertheless present. The stronger association for effort-dependent indices supports the idea that both components of ventilatory function contribute to the association with dementia. Therefore, it is very unlikely that decreased ventilatory capacity is related to dementia merely by factors outside the respiratory system.

We are currently unaware of any convincing explanation for this association, primarily because research in this field is sparse, and there are not enough data available from other sources (i.e., clinical, experimental, and basic research) to confirm this result. However, with regard to respiratory physiology, it is generally held that PaO₂ decreases with age ⁽²³⁾, but this was not confirmed for elderly persons with COPD by a recent report ⁽²⁴⁾. Interestingly, the authors found a positive relation of PaO₂ to FEV-1 and a negative relation to PaCO₂. Thus, a possible pathophysiological relation may exist by chronic hypercapnia or hypoxemia. In support of this hypothesis, hyperbaric oxygen application to patients with dementia resulted in surprising changes of cognitive function ⁽²⁵⁾. There is more recent evidence for a relation between sleep apnea, severe COPD, or aerobic training conditions and cognitive function that may point to similar mechanisms.

Clearly, these assumptions can only be proven by further clinical, physiological, and experimental data. These are needed to validate the obtained association, to identify its temporal direction, and to elucidate possible pathophysiological mechanisms.

	Acknowledgments

 
The research reported is part of the multidisciplinary Berlin Aging Study (BASE). BASE is conducted by the Committee on Aging and Societal Development of the Academy of Sciences and Technology in Berlin (1989–1993) and the Berlin-Brandenburg Academy of Sciences (since 1994) in collaboration with the Free University of Berlin and the Max Planck Institute for Human Development and Education, and is financially supported by Germany's Department of Research and Technology (Grants 13 TA 011 and 13 TA 011/A) and the Department of Family and Senior Citizens. We are indebted to Dr. E. Pleger for helpful advice on pulmonary function measures during the preparation of this article.

Received August 13, 1999

Accepted February 8, 2000

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