The association between chronic obstructive pulmonary
disease and
dementia: a population-based retrospective cohort study
W.-C. Liaoa,b, C.-L. Linc, S.-N. Changd, C.-Y. Tua,b and C.-H. Kaoe,f
Introduction
Chronic obstructive pulmonary disease (COPD) is
characterized by partially reversible airflow limitation
and usually progresses with chronic inflammation of
the airway that is caused mainly by cigarette smoking
and exposure to noxious gases [1], and is one of the
leading causes of morbidity and mortality worldwide.
COPD is predicted to become the third most common
cause of death and fourth most critical disabilityproducing
illness by 2020 [2].
Comorbidities of COPD contribute to overall severity
in individual patients. The most frequently
reported comorbidities are cardiovascular diseases,
including ischaemic heart disease, atrial fibrillation
and hypertension, as well as peptic ulcer, osteoporosis,
metabolic syndrome, diabetes and lung cancer [3,4].
Previous studies have indicated that COPD increases
the risk of cognitive impairment and neuropsychological
deficits [5]. The comorbidities of COPD increase
when patients experience hypoxia, impairment of gas
exchange or systemic inflammation, and intensify disabilities
[6]. Dementia is characterized by memory deficit and
impairment in at least one other cognitive function,
and together these cognitive deficits must result in
impaired performance of daily activities. Dementia is
common in later life, and its risk doubles every
5 years after 65 years of age [7]. Cognitive impairment
may be caused by hypoxia and inflammation, which
are associated with COPD [8,9].
Dementia is associated with increased mortality and
disability; however, its relationship with COPD
remains poorly understood [10]. The purposes of this
study were to verify the association between COPD
and dementia in the Taiwanese population and to
examine the relative risk of dementia in patients with
and without COPD.
Methods
Data sources
The data source was the Taiwan National Health
Insurance Research Database (NHIRD), a large computerized
administrative database maintained by the
Department of Health and the National Health
Research Institutes of Taiwan. The National Health
Insurance (NHI) program was established in 1995,
and nearly 99% of residents have been enrolled [11].
The database comprises comprehensive information
on clinical visits for each insured person, including
records of outpatient visits, hospital admissions, prescriptions,
disease status and diagnostic codes in the
format of the International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-CM).
For research purposes, the National Health Research
Institutes release all claims data to the public in an
electronic format, encrypt the patients’ personal information
for privacy protection, and provide researchers
with anonymous identification numbers associated
with the relevant claims information, including data
on the sex, date of birth, registration for medical
services and medication prescriptions of patients.
Patient consent is not required for accessing the
NHIRD. This study was exempted by the Institutional
Review Board of China Medical University in
Central Taiwan (CMU-REC-101-012).
The data used in the present study were derived from
a sub-dataset of the NHIRD that comprises all records
collected from 1996 to 2010 on 1 million randomly
sampled beneficiaries enrolled in the NHI in 2010.
Study participants
Patients with COPD newly diagnosed between 1998
and 2008 were identified in the database. The date of
the first diagnosis of COPD was used as the index
date. Patients with a history of dementia (ICD-9-CM
290, 294.1, 331.0) or who were younger than 20 years
of age were excluded. Finally, 20 492 patients with
COPD were selected to be the study patients and were
designated as the COPD cohort. For each COPD
patient, two non-COPD patients were randomly
selected from the same study period according to the
same exclusion criteria and were frequency-matched
with the COPD patients according to age and sex to
construct the non-COPD cohort, which comprised
40 765 patients.
Outcome measurement and comorbidities
Each study patient was followed until dementia was
diagnosed, and the patient was excluded for loss to
follow-up, death or withdrawal from the database, or
the end of 2010.
At the baseline, major comorbidities, such as diabetes
(ICD-9-CM 250), hypertension (ICD-9-CM 401–
405), stroke (ICD-9-CM 430–438), coronary artery
disease (CAD) (ICD-9-CM 410–414), depression
(ICD-9-CM 296.2, 296.3, 300.4 and 311) and head
injury (ICD-9-CM 850–854, 959.01), were considered
covariates.
Statistical analyses
The baseline characteristics of the COPD cohort and
non-COPD cohort were compared using the chisquared
test. The incidence densities of the two
cohorts were calculated according to sex, age and
number of comorbidities. To estimate the cumulative
incidence of dementia risk in the two cohorts, a survival
analysis was performed using the Kaplan–Meier
method, with significance based on the log-rank test.
Crude and adjusted hazard ratios (HRs) and 95%
confidence intervals (CIs) for factors associated with
the risk of dementia were estimated using Cox proportional
hazard regression models. All analyses were
performed using SAS statistical software for Windows
(Version 9.1; SAS Institute Inc., Cary, NC, USA),
and the significance level was set at 0.05.
Results
A total of 20 492 cases of COPD and 40 765 matched
control cases were selected from the NHIRD during
the defined period of interest. Of the COPD patients
and the non-COPD patients, 36.0% were 65–74 years
of age and 71.4% were male (Table 1). The COPD
cohort was more likely than the non-COPD cohort to
experience diabetes (22.4% vs. 18.5%, P < 0.0001), hypertension (62.5% vs. 46.9%, P < 0.0001),
stroke
(24.7% vs. 16.4%, P < 0.0001), CAD (40.4% vs.
22.4%, P < 0.0001), depression (5.52% vs. 3.20%,
P < 0.0001) and head injury (4.79% vs. 3.16%,
P < 0.0001). The mean follow-up time was 6.29
(SD 3.51) and 6.88 (SD 3.43) for the COPD cohort
and the non-COPD cohort, respectively (data not
shown).
Table 2 also shows the dementia incidence densities
in the COPD cohort and non-COPD cohort and the
COPD/non-COPD HRs for dementia. During the
observation period, 2553 patients in the non-COPD
cohort (incidence rate 9.11 per 1000 person-years)
and 1697 patients in the COPD cohort (incidence
rate 13.2 per 1000 person-years) developed dementia.
Figure 1 shows the cumulative incidence of dementia.
The risk of dementia was significantly higher for
patients with COPD than for patients without COPD
(log-rank P < 0.001). The results of the multivariate
analyses indicated that, compared with the nonCOPD cohort, the COPD cohort was associated with
a significantly higher risk of dementia (HR 1.27, 95%
CI 1.20–1.36).
In all analyses in which the patients were stratified
according to sex, age and the number of comorbidities,
the patients in the COPD cohort, particularly
female patients (HR 1.31, 95% CI 1.17–1.47) and
patients aged 65–74 years (HR 1.38, 95% CI 1.25–
1.52), were observed to be associated with an
increased risk of dementia (Table 2).
Table 3 illustrates the interactive effect of comorbidities
and COPD on outcome. A statistically significant
increased risk was observed for patients
diagnosed with both COPD and diabetes (HR 1.97,
95% CI 1.77–2.18; interaction P = 0.001). Interactions
of hypertension (HR 2.05, 95% CI 1.88–2.24; interaction
P = 0.03), stroke (HR 2.52, 95% CI 2.31–2.76;
interaction P = 0.006) and CAD (HR 1.65, 95%
CI 1.52–1.80; interaction P < 0.001) were also associated
with an increased risk of dementia.
The associations between dementia and the number
of emergency room visits and admissions for acute exacerbation (AE) of COPD are shown in Table
4.
AE resulting in more than five emergency room visits
was associated with a significantly higher risk of
dementia compared with the non-COPD cohort
(HR 41.7, 95% CI 22.3–78.0). In addition, the group
of patients who were admitted for AE of COPD
more than five times exhibited the highest risk of
dementia, with an adjusted HR of 196.8 (95%
CI 145.9–265.5).
Discussion
Our study is the first nationwide population-based
study to evaluate the association between COPD and
dementia. In this study, the overall incidence rate of
dementia was 1.32% higher in the COPD cohort
(HR 1.27) than in the non-COPD cohort after adjustment
for age, sex and comorbidities. A number of significant
interactions between covariate conditions and
COPD were noted to heighten risk for dementia. The
increased incidence was associated with the group experiencing a high frequency of exacerbations,
which
is consistent with the results observed in the severe
COPD group [12]. Therefore, it is suggested that
COPD increases the risk of developing dementia.
COPD is primarily caused by exposure of the
respiratory tract to noxious particles and gas inhalation
and causes airflow limitation and systemic
inflammation [13]. These comorbidities are critical
manifestations affecting organs other than the lungs
[14]. The effects of COPD on the neuropsychiatric
system have been described in recent years, and the
etiologies have been discussed [5,8]. Declining lung
function is associated with poorer performance in
cognitive assessments, and low pulmonary function in
midlife may be an early marker of subsequent cognitive
problems [15,16]. Cognitive impairment in
patients with COPD was associated with increased
mortality and disability [17]. Previous studies have
hypothesized that cigarette smoking, hypoxia and systemic
inflammation explain the association between
COPD and dementia [18,19].
Approximately 80%–90% of COPD patients have a
history of cigarette smoking. Controversially, cigarette
smoking is associated with an increased risk of
dementia [20,21]. Smoking may influence cognitive
function by exacerbating cerebral hypoxia [22]. Some
particles in cigarette smoke are thought to have a
direct neurotoxic effect and are linked to an increased
risk of Alzheimer’s disease [23].
Neuronal dysfunction in patients with COPD seems
to increase in patients with gas-exchange deficiency.
Hypoxia causes the consumption of neurotransmitters
because of the dysfunction of oxygen-dependent
enzymes [23]. Hypoxemic patients showed more deterioration
in cerebral perfusion and cognitive performance
than non-hypoxemic patients did [24].
The systemic inflammatory process observed in
COPD patients may contribute to the pathogenesis of
atherosclerosis and cardiovascular diseases [25]. In
addition, studies have reported that an increased number
of inflammatory markers may indicate some neurodegeneration
such as dementia [26,27].
Some studies discussed the association between
COPD and dementia. Rusanen et al. examined the
association between midlife and late-life self-reported
COPD and asthma and the lifelong risk of cognitive
impairment. They identified that midlife COPD and
asthma were associated with higher risk of mild cognitive
impairment (MCI) and dementia later in life [28].
The preliminary study by Villeneuve et al. [9] demonstrated
that a substantial proportion of patients with
COPD were found to have MCI. Singh et al. found
that COPD significantly increased the risk for MCI.
They also found a dose_response relationship such that
individuals with COPD duration of longer than 5 years
at baseline had the greatest risk for any MCI [29,30].
Our study revealed that patients with higher frequencies
of AE of COPD exhibit a higher incidence of
dementia. Exacerbations negatively affect life quality,
accelerate the decline of lung function and are associated
with mortality and high socioeconomic costs [31–
33]. Because forced expiratory volume in 1 s (FEV1)
does not accurately represent the severity of COPD,
the frequency of AE and FEV1 have been used
equally to evaluate the severity and risk of COPD
since 2011 [12]. In one study, exacerbations became
more frequent as the severity of COPD increased, and
the increased rate of exacerbation appears to reflect an independent susceptibility [34]. This finding
is consistent
with our observation that patients with more
frequent AE (representing greater severity of the disease)
exhibit a higher incidence of dementia. A
dose_response relationship existed between the severity
of COPD and dementia.
The strength of our study is the use of populationbased
data that are highly representative of the general
population. However, certain limitations to our findings
should be considered. First, the NHIRD does not
contain detailed information regarding body weight,
smoking habits and lifestyles, which may be potential
comorbidities or risk factors for dementia. Secondly,
the evidence derived from a retrospective cohort study
is generally lower in statistical quality than that from
randomized trials because of potential biases related to
adjustments for confounding variables. Despite our
meticulous study design and control measures for confounding
factors, biases resulting from unknown confounding
variables may have affected our results.
Thirdly, all data in the NHIRD are anonymous. Thus,
relevant clinical variables such as imaging results and
serum laboratory data were unavailable for our study
cases. However, Taiwan launched an NHI program
operated by a single-payer, the government, in 1995.
All insurance claims are scrutinized by medical reimbursement
specialists and subject to peer review.
Therefore, the data regarding the diagnoses for COPD
and dementia were reliable. Fourthly, the Alzheimer
type or other types of dementia, such as vascular
dementia, cannot be exactly and accurately differentiated
from dementia in the NHIRD because there is no
information available from the diagnostic codes of
ICD-9-CM. Therefore, in this study they are included
in all types of dementia.
Conclusion
In conclusion, this nationwide retrospective cohort
study demonstrated that COPD is associated with a
higher future risk of dementia after adjusting for diabetes,
hypertension, CAD, head injury and depression.
Higher frequencies of AE predict a higher risk of
dementia development. The detailed pathophysiology
may require further clarification in prospective studies.
It is crucial to prevent the development of COPD and to
effectively treat COPD to prevent the development of
dementia.