Cognitive dysfunction in patients with chronic obstructive pulmonary disease--a systematic review.

Abstract

Substantial healthcare resources are spent on chronic obstructive pulmonary disease (COPD). In addition, the involvement of patients in monitoring and treatment of their condition has been suggested. However, it is important to maintain a view of self-care that takes differences in cognitive ability into account. The aim of this study was to determine the occurrence and severity of cognitive dysfunction in COPD patients, and to assess the association between severity of COPD and the level of cognitive function.
We conducted a systematic review, and a search in the following databases: Medline, PsychINFO, Cochrane Library, EMBASE, CINAHL, and SweMed up to July 2010. The articles were included if participants were patients with COPD, relevant outcome was cognitive function investigated by a neuropsychological test battery, and the severity of COPD had been assessed.
Fifteen studies were included, involving 655 COPD patients and 394 controls. Cognitive function was impaired in COPD patients as compared to healthy controls, but the level of functioning was better than in patients with Alzheimer's disease. There was a significant association between severity of COPD, as measured by lung function and blood gases, and cognitive dysfunction, but only in patients with severe COPD.
Cognitive impairment can be detected in severe COPD patients, but the clinical relevance of the cognitive dysfunction is not yet known. Future studies should concentrate on the consequences of cognitive dysfunction for daily living in these patients, and solutions involving a high degree of self-care might require special support.

Full text

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REVIEW
Cognitive dysfunction in patients with chronic
obstructive pulmonary disease e A systematic
review
Lone Schoua,*, Birte Østergaardb, Lars S. Rasmussenc,
Susan Rydahl-Hansend, Klaus Phanaretha
aTelemedicine Research Unit, Frederiksberg University Hospital, Nrd. Fasanvej 57, 2000 Copenhagen F, Denmark
bResearch Unit of Nursing, Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark
cDepartment of Anesthesia, Centre of Head and Orthopaedics, Rigshospitalet, University Hospital of Copenhagen,
2100 Østerbro, Denmark
dResearch Unit of Clinical Nursing, Bispebjerg and Frederiksberg University Hospital, 2200 Copenhagen N, Denmark
Received 4 November 2011; accepted 23 March 2012
KEYWORDS
COPD;
Cognitive function;
Neuropsychological
tests;
Exacerbation;
Activities of daily
living;
Severity of COPD
Summary
Background: Substantial healthcare resources are spent on chronic obstructive pulmonary
disease (COPD). In addition, the involvement of patients in monitoring and treatment of their
condition has been suggested. However, it is important to maintain a view of self-care that
takes differences in cognitive ability into account.
The aim of this study was to determine the occurrence and severity of cognitive dysfunction
in COPD patients, and to assess the association between severity of COPD and the level of
cognitive function.
Methods: We conducted a systematic review, and a search in the following databases: Medline,
PsychINFO, Cochrane Library, EMBASE, CINAHL, and SweMed up to July 2010. The articles were
included if1participants were patients with COPD,2relevant outcome was cognitive function
investigated by a neuropsychological test battery, and3the severity of COPD had been
assessed.
Abbreviations: BADL, basic activities of daily living; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume (in the
first second), FVC; forced vital capacity, IADL; instrumental activities of daily living, MDB; Mental Deterioration Battery, MMSE; mini mental
state examination, MRI; magnetic resonance imaging, PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; PICO,
participants, interventions, comparisons, outcome; PRISMA, preferred reporting items for systematic reviews and meta-analyses; SaO2,
arterial oxygen saturation of hemoglobin.
* Corresponding author. Tel.: þ45 3816 4278.
E-mail address: loneschou@yahoo.dk (L. Schou).
+ MODEL
Please cite this article in press as: Schou L, et al., Cognitive dysfunction in patients with chronic obstructive pulmonary disease e A
systematic review, Respiratory Medicine (2012), doi:10.1016/j.rmed.2012.03.013
0954-6111/$ - see front matter ª 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2012.03.013
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Respiratory Medicine (2012) xx, 1e11

Page 2

Results: Fifteen studies were included, involving 655 COPD patients and 394 controls. Cogni-
tive function was impaired in COPD patients as compared to healthy controls, but the level
of functioning was better than in patients with Alzheimer’s disease. There was a significant
association between severity of COPD, as measured by lung function and blood gases, and
cognitive dysfunction, but only in patients with severe COPD.
Conclusions: Cognitive impairment can be detected in severe COPD patients, but the clinical
relevance of the cognitive dysfunction is not yet known. Future studies should concentrate
on the consequences of cognitive dysfunction for daily living in these patients, and solutions
involving a high degree of self-care might require special support.
ª 2012 Elsevier Ltd. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Occurrence and severity of cognitive dysfunction in patients with COPD . . . . . . . . . . . . . . . . . . . . . . . . . 00
Relationship between severity of COPD and cognitive dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Neuropsychological tests used and definition of “cognitive dysfunction” . . . . . . . . . . . . . . . . . . . . . . . . . 00
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Introduction
Chronic obstructive pulmonary disease (COPD) affects up to
600 million people worldwide and it is currently one of the
leading causes of morbidity and mortality in patients
suffering from chronic diseases. The prevalence of COPD
increases with age, and globally there is a growing number
of people who are more than 65 years old,1and major
healthcare resources are spent on COPD, with 50% of costs
accounted for by hospital stays.2In addition, the demand
for home care services has increased, and patients should
be involved in monitoring and treatment of their disease in
co-operation with the health professionals.3
However, it is important to maintain a view of self-care
that takes differences in cognitive ability into account. The
literature indicate that cognitive dysfunction could be
a limitation in patients with COPD.4Therefore, the level of
cognitive functioning of these patients must be taken into
consideration before self-care can be planned and tailored
toward the patient’s individual capability and needs.5
COPD is not only characterized by progressive and
largely irreversible limitation of air flow, shortness of
breath, cough, and expectoration.6In addition, brain
function may be adversely affected by COPD, and magnetic
resonance imaging (MRI) has shown altered cerebral
perfusion in patients with COPD who have cognitive
dysfunction as a clinical manifestation.7The relationship
between the many processes involved in an everyday
cognitive task is complex, but cognitive ability is usually
broken down into domains concerning memory, learning
ability, attention/concentration, abstract thinking, and
problem solving.4Cognitive dysfunction reduces the level
of functioning as assessed by activities of daily living,8,9and
it is associated with poor compliance with both medication
and oxygen therapy, and poor compliance increases the risk
of acute exacerbation.10,11
Hypoxemia and hypercapnia appear to aggravate cogni-
tive dysfunction in patients with COPD,12and in a multi-
center study of 302 patients with mild, moderate and severe
hypoxia, the frequency of cognitive dysfunction was 27% in
patientswithmildhypoxiaand61%inpatientssufferingfrom
severe hypoxia. Increasing age and low level of education
were also associated with cognitive impairment.13Further-
more, a direct association between cerebral hypo-perfusion
and cognitive dysfunction has been described.7,14In addi-
tion, cognitive performance might also be affected in
patients with normaloxygensaturation.15An association has
also been described between cognitive impairment and
fatigue, and increased need for sleep in patients with severe
COPD.16Also, McSweeny and colleagues discovered that
cognitive dysfunction in patients with COPD was closely
related to impaired functioning in daily life.17
In a previous systematic review of patients with COPD
the authors concluded that these patients may function at
a reduced level of cognition, and that cognitive impairment
is associated with a lower quality of life depending on the
study design, the neuropsychological tests used, and
sample size.4The review included 81 studies encompassing
2 L. Schou et al.
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Page 3

multiple psychological characteristics or dimensions, 25 of
which included assessments of cognitive function, pub-
lished between 1966 and 2004. Six out of 25 studies only
used the Mini Mental State Examination (MMSE) to evaluate
cognitive function, and they found no impairment.4
However, the MMSE is developed
dementia,18and MMSE as a single test might fail to detect
more subtle forms of cognitive impairment.19In addition,
the severity of the disease was only reported in one study.
It is therefore difficult to investigate a possible relationship
between the severity of COPD and the degree of cognitive
dysfunction, and more importantly, the potential conse-
quences for the patient’s daily life.
The aim of this study was to determine the occurrence
and severity of cognitive dysfunction in patients with COPD,
based on a systematic review of the literature. Further-
more, we wanted to determine the association between
the severity of COPD and the level of cognitive function.
for screening for
Methods
Search strategy
We adopted a systematic approach based on the guidelines
set out by the Centre for Review and Dissemination,
University of York (2001),20but a systematic search strategy
was furthermore initiated based on the PICO (Participants,
Interventions Comparisons, Outcome) framework to iden-
tify core concepts, facets, and keywords for searching of
electronic databases.21
The strategy was customized for each database and
included controlled vocabulary, such as the National Library
of Medicine MeSH and keywords, to identify relevant
studies for this review. We systematically searched the
following databases: Medline/PubMed, PsychINFO, the
Cochrane Library, EMBASE, CINAHL, and SweMed up to July
2010. The search was conducted using the following
keywords: COPD, Chronic Obstructive Pulmonary Disease,
Pulmonary Disease, Chronic Obstructive [MeSH], Neuro-
psychological tests [MeSH], Psychomotor Disorders [MeSH],
Cognitivefunction, Cognitive
impairments, Cognitive performance, and Brain perfusion.
dysfunction,Cognitive
Selection criteria
The selection of studies was done systematically. Following
an initial examination of title and abstract, full-text arti-
cles were retrieved independently by first and second
authorforfurther examination
reviewers compared their selections of included studies,
and any disagreements were discussed and resolved by
consensus. The articles were critically evaluated and
included in this review if they met the following criteria. 1.
Participants were identified as patients with COPD. 2.
Relevant outcome was cognitive function, investigated by
a neuropsychological test battery, describing memory,
attention/concentration, abstract thinking, mental flexi-
bility, and learning ability. 3. The severity of COPD was
assessed by lung function and/or blood gases.
Because the aim of this study was to investigate the
occurrence of cognitive dysfunction in patients with COPD,
and selection.The
we did not include any studies investigating the effect of an
intervention. Studies only using the Mini Mental State
Examination (MMSE) were excluded because the MMSE has
a low sensitivity in relation to slight impairment18and the
diagnostic accuracy of the instrument has been found to be
lowerinpatientswithCOPDthaninthegeneralpopulation.22
The PRISMA checklist (2009) was used to make an
attempt to report the results systematically.23
Results
The literature search was finalized in July 2010, and we
identified a total of 273 abstracts (Fig. 1). Twenty-five
additional abstractswere
searches. A total of 39 full-text articles, published between
1982 and 2009, were identified and 24 studies were
excluded. The reasons for exclusion were1the use of MMSE
as a single test to evaluate the patients’ cognitive function
(nine studies),2investigation of auditory and visually evoked
potentials, using a Cadwell Spectrum 32 recording instru-
ment (two studies),3using only driving simulator test (one
study).4no description of COPD severity for the patients
included (three studies), and5investigation of the effect of
different kinds of interventions in relation to COPD (six
studies). Two studies were excluded because they were
reviews of previously published studies included in this
review, and one study was excluded because it was only
a protocol. Fourteen original studies (15 references) were
included inthisreview,and nineof them11,15,16,19,24e28were
included in a former review by Hynninen et al. from 2005.4
All fourteen studies used a neuropsychological test battery
(Table 1).
Of the fifteen studies included in this systematic
review, ten were designed as “case-control studies”, nine
of which included healthy volunteers; three of these
studies had mixed control groups and one study only had
patients with chronic cerebral vascular disorders as
a control group. One study used a prospective cohort
design,12
and the last four studies used descriptive
designs.8,16,25,28The total numbers of study participants
were 655 patients with COPD and 394 controls. Mean age
of the study participants was 63.9 years. Information
about gender distribution was available for 14 studies, and
one study was conducted with males only. The severity of
COPD was described in all fifteen studies and ranged from
moderate to very severe COPD.
The main content of and methodological details from
the relevant articles were extracted and tabulated into
a matrix (Table 2), with information organized under the
headings: author, year, design, sample (severity of COPD),
neuropsychological test instruments used, definition of
cognitive dysfunction, occurrence and severity of cognitive
dysfunction, and correlation between severity of COPD and
cognitive dysfunction.
identified throughhand
Occurrence and severity of cognitive dysfunction in
patients with COPD
Eight case-control studies found significant impairment in
cognitive performance in half of the tests used compared to
healthy controls.7,11,15,19,26,27,29,30
In two case-control
Cognitive dysfunction in patients with COPD3
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studies, the impairment was not statistically signifi-
cant.24,31
The occurrence of cognitive dysfunction in
patients with COPD was determined in only two studies12,26
d to be 17 patients (48.5%) and 13 patients (10.4%) d using
the Mental Deterioration Battery, a global battery of tests
assessing verbal intelligence, short-term verbal memory,
immediate visual-spatial memory, visual-spatial intelli-
gence, and constructional abilities.
With regard to the severity of cognitive dysfunction,
three studies compared patients with COPD to patients with
Alzheimer disease,11,19,26and the patients with COPD per-
formed significantly better in cognitive tests, but the test
results from these patients were comparable to data
obtained from patients with multi-infarct dementia.26
Antonelli-Incalzi et al. found that patients with COPD
had a significantly lower level of functioning in one of 13
cognitive tests, namely the “copying drawing with land-
marks”.12In a later study, they found significant differ-
ences in cognitive function in five of 12 cognitive tests;
visual-spatialintelligence,
verbal memory, copying drawing with landmarks, and
immediate visual memory.8In the remaining three studies,
a mild, cognitive impairment was found that was not
statistically significant,16,25,28and in two studies the find-
ings were compared with normative data.16,25
Regarding cognitive domains, memory7,8,11,16,24,27,29,31
and attention7,8,11,15,24,27,30are shown to be the most influ-
enced domains in most of the studies. Also speed, coordi-
nation and learning abilities are affected,7,15,27see Table 2.
verbal fluency, short-term
Relationship between severity of COPD and
cognitive dysfunction
The
severity of COPD was measured in relation to lung function
(FEV1, FEV1/FVC) and/or blood gases (PaO2, PaCO2, SaO2).
None of the three studies that included patients with
moderate COPD found any significant association with
severity of COPD.19,24,30In the group of studies investi-
gating patients with severe to very severe COPD (according
to GOLD guidelines), eight of 12 studies found that these
patients’ cognitive impairments were significantly associ-
ated with the severity of COPD.7,15,16,25e29The remaining
four studies found no association between severity of COPD
and cognitive dysfunction,31or it was not assessed8,11,12,31).
relationshipbetween cognitive dysfunctionand
Neuropsychological tests used and definition of
“cognitive dysfunction”
All 15 studies included a battery of neuropsychological
tests. The tests used measured visual and verbal memory
(immediate and delayed recall), attention, concentration
and speed, visual-spatial intelligence, constructive func-
tions etc. (see Table 1).
A clear theoretical definition of “cognitive dysfunction”
that is appropriate for patients with COPD have not been
generally accepted. In consequence, different studies use
different operational definitions. For example, one author
Records identified through database
searching
(n = 273)
Additional records identified
through other sources
(n = 25)
Records screened
(n = 298)
Records excluded
(n = 259)
Full-text articles assessed
for eligibility
(n = 39)
Full-text articles excluded
(n = 24)
Studies included
(n = 15)
Figure 1
Flow diagram of the inclusion process.
4 L. Schou et al.
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of three articles has defined “cognitive dysfunction” as
a defective performance of more than four components of
the Mental Deterioration Battery (MDB)".11,12,26One study
defined cutoff means scores for dementia.28The definition
used in five other studies was a deterioration of at least one
standard deviation (SD) in at least one measure compared
to the normative mean.7,8,16,24,31In the rest of the
remaining six studies included, no specific definition of
cognitive dysfunction was given (Table 2).
Discussion
The aim of this review was to determine the occurrence
and severity of cognitive dysfunction in patients with COPD.
The occurrence of cognitive dysfunction was only reported
in two studies, being 48.5%26and 10.4%.12With regard to
the severity of cognitive dysfunction, the finding shows that
cognitive function is impaired in patients with COPD as
compared to healthy controls. Compared to patients with
Alzheimer’s disease, patients with COPD performed signif-
icantly better,11,19,26but the test results from COPD
patients were comparable to data obtained from patients
with multi-infarct dementia. Alzheimer’s disease and multi-
infarct dementia are serious brain disorders, and perhaps
not the most relevant groups with which to compare
patients with COPD. But there is a lack of more useful
comparison studies comparing COPD patients with, for
example, those with diabetes32or chronic heart failure,33
which also show cognitive impairment.
We were unable to assess the effect of cognitive
dysfunction on the daily life of patients with COPD.
However, the information about the positioning of patients
with COPD between that of the healthy controls and that of
patients with Alzheimer’s disease illustrates the difficulties
experienced by these patients.
We found a significant relationship between the severity
of COPD and cognitive dysfunction only in patients with
severe to very severe COPD. Patients’ cognitive impair-
ments were significantly associated with the severity of
COPD. Our findings contrast with the results of a review
from 2010,34where there was no significant relationship
between cognitive impairment and the severity of COPD,
but they also included fewer studies with patients with
severe to very severe COPD and accepted studies that used
MMSE as the only test.
The strength of this review is that we critically evaluated
the definitions of “cognitive dysfunction” and the neuro-
psychological tests used in all the studies included. Further-
more, we compared the results to those in other groups of
patients when possible, and not only to those in healthy
controls, in order to gain an understanding of the degree of
cognitivedysfunction.One limitation ofthepresentreview is
publication bias, because only published studies were
included. Another limitation is that several studies had small
sample size, and the severity of COPD is not always well
described. The included studies use a large variation in the
batteries of cognitive tests, and most of the studies did not
presentanexplicitdefinitionofclinicallymeaningfuleffects.
There is a distinct lack of information on the strategies for
screening for cognitive impairment in patients with COPD.
Only one author discussed the neuropsychological tests that
are available for these patients, and in earlier studies,26,35
this author made an effort to develop and validate exist-
ing tests to find a battery of tests that would detect more
subtle cognitive difficulties in patients with COPD.
Neuropsychological test batteries consist of many single
tests that each gives several variables, either scores or time
Table 1
Domains and cognitive tests.
DomainCognitive test (name)
Memory and learning
(Immediate memory)
(Delayed memory)
(Verbal memory)
(Nonverbal memory)
(Learning)
Memory efficiency test
Wechsler memory
scale-revised
VLMT
Ray’s auditory verbal
memory test
Story recall
Selective reminding test
Mental deterioration battery
Attention
(Simple attention)
(Selective attention)
(Sustained attention)
(Focused attention)
Digit span subtest
WRG S5
Cognitrone S2
WDG
Stroop color word test
Intelligence
ZVT, MWT
Wechler’s adult
intelligence scale
Wide range achievement
test ?3
Groningen intelligence test
Information processing
speed and coordination
Trail making test e B
HalstadeReitan test
battery for adults
TAP
Grooved pegboard test
Speech sounds perceptions
test
Lafayette repeatable
test battery
Finger tapping test
Verbal fluency
Controlled oral word
association test
Animal naming test
Sentence construction
Aphasia screening test
Boston naming test
Animal name fluency test
Verbal fluency
Mental deterioration battery
Visual attention
(Visual-spatial intelligence)
(Visuospatial scanning ability) Color trail test
(Visual exploration)
Raven progressive matrices
Benton visual retention test
Albert’s test
Copying drawings
Mental deterioration battery
Auditory attention
Seashore rhythm test
Conceptual function
Wisconsin card sorting test
Cognitive dysfunction in patients with COPD5
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Table 2
The studies on cognition and COPD that were included.
Study DesignSample: COPD Cognitive tests Definition of cognitive dysfunction/Occurrence
and severity of cognitive dysfunction
Relationship between
severity of COPD and
cognitive dysfunction
Fioravanti et al.,
199524
Case-control
study
N Z 50 patients
with COPD
(Moderate)
50 controls
(chronic cerebral
vascular
disorders)
Memory efficiency test Definition: Mean below age-matched normal
population.
About 30% of the COPD patients
show memory impairment, which was
confined to immediate memory?
COPD patients’ different aspects of memory
scores fell between the normal scores and
the more impaired CCVD (control group) scores.
Definition: Not described.
In 1 (letter fluency) out of 14 tests, the
patients with COPD performed significantly
worse than patients from the normal controls.
COPD patients were significantly better
than patients with Alzheimer’s disease in 13 tests.
Respiratory parameters
and memory efficiency
were correlated.
Kozora et al.,
199918
Case-control
study
N Z 32 patients
with COPD
(Moderate)
Controls: 31
normal subjects
31 mild
Alzheimer
Wechsler memory
scale-revised
Digit span subtest
Trail making test e B
Controlled oral word
association test
Animal naming test
Boston naming test
ZVT, MWT
VLMT
WRG S5
Cognitrone S2
WDG
TAP
No significant
correlation.
Orth et al.,
200630
Case-control
study
N Z 32 patients
with COPD
(Moderate)
10 healthy
controls
Definition: Not described.
Patient with COPD had significantly worse
results in 14 out of 20 tests, compared
with healthy controls. Domains as
intelligence and attention were
significantly impaired, while memory,
speed and coordination were not.
Definition: MDB e a “defective performance”
of more than four components of the mental
deterioration battery.
48.5% of the patients with COPD had cognitive
impairment, especially in the memory domain.
There was significant difference in 14 out of
19 cognitive tests, compared with normal adults.
Patients with COPD were comparable to patients
with MDI, and better than those with Alzheimer’s
disease in 13 out of 19 tests.
Definition: MDB - a “defective performance” of
more than four components of the mental
deterioration battery.
The global cognitive performance assessed
by MDB was significantly better than in Alzheimer
patients (p < 0.001), but significantly inferior to
that of the remaining two normal groups
No significant
correlation.
Antonelli-Incalzi
et al.,199326
Case-control
study
N Z 36 patients
with COPD
(Severe)
Controls:
49 normal adults
26 Alzheimer
28 Multiinfarct
Dementia (MDI)
Mental deterioration
battery
Cognitive impairment
was significantly and
positively correlated
with duration of
chronic respiratory failure
(p < 0.05).
Antonelli-Incalzi
et al., 199711
Case-control
study
N Z 42 patients
with COPD
(Severe, very
severe)
Controls:
27 normal adult
31 Alzheimer
Mental deterioration
battery
Ray’s auditory verbal
memory test
Wechler’s adult
intelligence
Scale-Revised
Not analyzed.
6
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26 older normal
subjects
(p < 0.0001).
In the rest of the 14 tests, patients with COPD were
significantly impaired in 6 out of 14 tests, including
memory and attention, compared with normal
adults, but in 10 out of 14 tests patients with COPD
scored significantly better than the Alzheimer
patients.
Definition: MDB - a “defective performance” of
more than four components of the mental
deterioration battery.
The prevalence of overall cognitive impairment,
expressed by MDB, was 10.4%.
In the subtests, the prevalence of the patients’
abnormal performance change between 2 and 40%.
The only significant test results were the
“Copying drawings with landmarks” test, that
refers to visual attention (p < 0.02).
Definition: Raw cognitive scores were corrected
for age and education and compared with data
from a reference population.
52/149 patients (35%) had significantly lower
cognitive performance in 5 out of 12 tests.
Visual attention, verbal fluency and memory
were the most affected domains.
Antonelli-Incalzi
et al., 200612
Prospective
cohort study
N Z 134 patients
with COPD
(Severe)
105 servivors
29 non-survivors
Mental deterioration
battery
Not assessed.
Antonelli-Incalzi
et al., 20088
Descriptive
study
N Z 149 patients
with COPD
(Severe).
High (H), mid
(M) and low (L)
level of cognitive
function
Raven Progressive
matrices
Verbal fluency
Verbal memory
Albert’s test
Copying drawings
Wechsler
Sentence construction
Wide range achievement
test 3
Wechsler memory scale
Wechsler adult
intelligence scale
Not assessed.
Borson
et al., 200829
Case-control
study (pilot)
N Z 18 patients with
COPD(Severe, very
severe) 9 healthy
controls
Definition: Not described.
Patients with COPD differed significantly from
healthy
controls in some of the intelligence (p < 0.03) and
memory (p < 0.05) tests, but not in all.
Lower scores in
patients with
oxygen-dependent
COPD vs. non-oxygen-
dependent
patients on cognitive
measures.
All the patients in this
study had end-stage
COPD.
Crews et al.,
200116
Descriptive
study
N Z 47 patients
with COPD (Severe,
very severe)
Wechsler adult
intelligence scale
Wechsler memory scale
Trail marking test
Wisconsin card sorting test
Selective reminding test
Definition: Test scores were more than one standard
deviation (SD) below their respective normative
means.
In 2 out of 24 cognitive tests, over 52% of the
patients with COPD were impaired (Selective
Reminding Test e that refers to memory).
In all other tests, 0e44% of the patients had
impaired cognitive function.
(continued on next page)
Cognitive dysfunction in patients with COPD
7
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Table 2 (continued)
StudyDesign Sample: COPD Cognitive testsDefinition of cognitive dysfunction/Occurrence
and severity of cognitive dysfunction
Relationship between
severity of COPD and
cognitive dysfunction
Fix et al.,
198225
Descriptive
study
N Z 66 patients
with COPD (Severe)
Wechsler adult
intelligence scale
Benton visual retention test
Trail marking test
Speech sounds perceptions
test
Stroop color word test
Seashore rhythm test
Stroop color word test
Trail making test
Story recall
Groningen intelligence test
Wechsler adult intelligence
scale
Definition: Not described.
Mild, but not significant, cognitive impairment in
6 out of 16 cognitive tests, compared to normal
range.
3 out of 13 tests
correlated
significantly.
Liesker et al.,
200415
Case-control
study
N Z 30 patients
with COPD (Severe)
20 healthy controls
Definition: Not described.
Patients with COPD scored significantly worse than
healthy controls in 3 (speed and coordination,
attention, and intelligence) out of 9 cognitive tests.
Patients with lower
FEV1(<50% pred.)
tended to score worse
than those with higher
FEV1(>50% pred.),
but this was only
significant in 1 out of
9 tests.
Cognitive dysfunction
was correlated with
resting partial
pressure of oxygen.
Prigatano et al.,
198327
Case-control
study
N Z 100 patients
with COPD (Severe)
25 healthy controls
HalstadeReitan test battery
for adults
Trail making test
Aphasia screening test
Wechsler memory scale
Wechsler adult intelligence
scale
Lafayette repeatable
test battery
Wechsler Memory
Scale-Revised
Color Trail test
Grooved Pegboard Test
Definition: Not described.
In 26 out of 40 cognitive tests, patients with COPD
were significantly impaired, compared to healthy
controls. The most affected domains were; Speed
and coordination, memory and learning,
intelligence and attention.
Shimet al.,
200131
Case-control
study
N Z 17 patients
with COPD (Severe)
6 hypercapnia/
11 non-hypercapnia
21 healthy controls
Definition: 2 SDs below the standardized values.
Mean values for patients with COPD were below
standardized values for all 9 cognitive parameters.
But only in three tests (general- and verbal memory,
and delayed recall), the COPD patients were
2 SDs below the standardized values.
Definition of dementia: the cutoff mean scores for
dementia are 123.
In the Dementia Rating Scale, 1 out of 18
patients were below cutoff mean score.
In the rest of the 31 tests, there were no
significant differences.
No significant
correlation.
Stuss et al.,
199728
Mixed
decriptive
study
N Z 18 patients
with COPD
(Severe)
Dementia rating scale
Wechsler adult
intelligence scale revised
Aphasia screening test
Boston naming test
Animal Name fluency test
Finger tapping test
Wechsler memory scale
Wisconsin Card sorting test
Significant relationship
between blood gases
and cognitive measures
of memory and
attention capacity.
8
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Page 9

measurements. However, when initiating a study, it is
necessary to decide which variables should be considered
for evaluation of cognitive function,36and more impor-
tantly the definition of the “dysfunction” and the statistical
data analysis methods to be used.
When one examines the literature, the crucial step in
finding a significant neurocognitive deficit is in determining
the definition itself. The definition of a significant deficit
varies, and the lower the threshold of “deficit” is deter-
mined to be, the larger number of patients will be that have
a deficit.37Only the studies by Antonelli-Incalzi and
colleagues presented a specific definition of “cognitive
dysfunction”, which was “defective performance of more
thanfour componentsof
battery”.11,12,26
The clinical relevance is also important to discuss. In
some of the studies reviewed, only some of several tests
was found to be significantly altered. Statistically signifi-
cant differences between groups may not be clinically
relevant, and the consequences are also difficult to eval-
uate in terms of the patient’s daily life, including daily
activities, self-care behavior, anxiety, and depression. A
difference of just a few seconds in the performance of
neuropsychological tests may be statistically significant due
to a large study group, but is may be of no clinical impor-
tance.36In most patients, the deficit may not matter in
functional terms. Apparently, many activities of daily living
do not require the level of performance called for during
neuropsychologicaltesting.
decline in test performance and functional decline is also
apparent in the methodological difficulties of defining
a cognitive deficit or dysfunction.38
Accordingly, it is still not possible to conclude that
adetecteddeficitincognitivefunctionisrelatedtoaclinical
disability in performing self-management and self-care.
Only one study, by Antonelli-Incalzi and colleagues
(2008), focused on the consequences of the patients’
cognitive dysfunction for daily living, as assessed by Basic
Activities of Daily Living (BADL) scales and Instrumental
Activities of Daily Living (IADL) scales. In this study, with 149
patients with severe COPD in three clusters e a high, middle,
or low level of cognitive functioning, based on 11 neuro-
psychological scores e the authors found an association
between cognitive dysfunction and need for support in basic
daily activities, such as medication, getting dressed, and
managing money. The majority of patients who were
enrolled were around 65 years old, and 135 out of 145
patients were men. Overall, there was dependency in at
least one BADL domain in 39.6% of patients and in one IADL
domain in 65.8% of patients. Altogether, 27.5% were depen-
dentinoneormore IADLdomains,butnotinBADL;fromthis,
the authors concluded that the patients were able to live at
home with some support. Altogether, 16.1% were dependent
in one to five IADL domains but not in any BADL domain,
which corresponds to a greater need for support. Finally,
about one in every five patients was dependent on external
help in one to five IADL domains and in more than one BADL
domain, and needed support for several hours a day.8
But the association between cognition and activities are
still weak, and a causal relationship has not yet been
demonstrated. In COPD patients, IADL are more likely to be
affected by deconditioning, systemic inflammation and
the mental deterioration
The discrepancybetween
Ortapamuk et al.
20067
Case-control
study
N Z 18 patients
with COPD (Severe,
very severe)
(8 hypoxemia/
10 non-hypoxemia)10 healthy controls
Mental deterioration battery
Wechsler memory
scale-revised
Color trail test
Grooved Pegboard test
Definition: Mean below age-matched normal
population. Non-hypoxemic patients with COPD
were similar to healthy controls in cognitive
performance. Hypoxemic patients performed
worse than the two other groups, but the resultwas only significant in 5 (p < 0.01) out of 21 tests.
The domains were verbal and visual memory,
attention, concentration and delayed recall.
Hypoxemic patients
showed more
deterioration
in cognitive
performance than
non-hypoxemic
patients.
Cognitive dysfunction in patients with COPD9
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Page 10

dynamic hyperinflation, than cognition. In addition, 135 of
the 145 patients were men; this is not comparable with the
distribution of these patients in general, where women
account for at least 50% of the total.
The most affected cognitive domains in this review were
memory and attention, but also speed, coordination and
learning abilities were reduced in COPD patient. This
impairment might have important clinical and healthcare
implications in patients with COPD. Therefore, the level of
cognitive functioning of these patients must be taken into
consideration before self-care can be planned and tailored
toward the patient’s individual capability and needs.
Cognitive dysfunction could resulting in a risk of acute
exacerbation, and reduced function in several basic activ-
ities of daily living.9e11,39McSweeny and colleagues17also
found that cognitive dysfunction was more closely related
to impaired functioning in daily life than to emotional
functioning in patients with COPD. This is in line with Orth
et al. who discovered that the frequency of accidents in
simulated driving situations is significantly increased in
patients with COPD,40which might influence future legis-
lation regarding driving licenses.
Conclusions
This systematic review has shown that cognitive function is
impaired in patients with COPD as compared to healthy
controls, but the level of functioning appears to be better
than in patients with Alzheimer’s disease.
We found an association between severity of COPD and
cognitive dysfunction in patients with severe to very severe
COPD.
The clinical importance of the cognitive impairments is
hard to gauge due to the heterogeneity of outcome
measures and lack of consistent definition of cognitive
dysfunction in the reviewed studies. Future studies should
concentrate on the consequences of cognitive dysfunction
for daily living in these patients. Also, in patients with
severe and very severe COPD, solutions involving a high
degree of self-care might require special support.
Conflict of interest
The authors report no conflicts of interest to disclose. The
authors alone are responsible for the content and writing of
the paper. All authors have read and accepted the
manuscript.
Acknowledgments
This study was supported financially by “The Tryg Founda-
tion” and “The Health Insurance Foundation” (non-
commercial).
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