Cognitive Impairment in Chronic Obstructive Pulmonary Disease and Chronic Heart Failure: A Systematic Review and Meta-analysis of Observational Studies

JAMDA xxx (2017) 1.e1e1.e11

JAMDA journal homepage: www.jamda.com

Review Article

Cognitive Impairment in Chronic Obstructive Pulmonary Disease and Chronic Heart Failure: A Systematic Review and Meta-analysis of Observational Studies Abebaw M. Yohannes PhD, MSc, FCCP a, *, W. Chen PhD, MPH, MSc b, Ana M. Moga MSc c, I. Leroi MD d, Martin J. Connolly MD e a

Manchester Metropolitan University, Manchester, United Kingdom University of British Columbia, Vancouver, Canada McGill University, Montreal, Canada d The University of Manchester, Manchester, United Kingdom e The University of Auckland and Waitemata District Health Board, Auckland, New Zealand b c

a b s t r a c t Keywords: COPD CHF mild cognitive impairment dementia prevalence

Background: Cognitive impairment is common in people living with chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF); however, accurate estimates of prevalence are lacking. To date, there are no meta-analyses that have specifically investigated prevalence of mild cognitive impairment (MCI) in this particular population. Our aim was to undertake a systematic review and apply meta-analytic methods to estimate the prevalence of MCI and any cognitive impairment (ACI) in people with COPD and CHF. Methods: We identified relevant studies for COPD and CHF by searching the published literature from inception to February 2016 using the MEDLINE and Web of Science databases. Studies were included if they documented the prevalence of MCI and/or cognitive impairment for COPD and CHF patients without dementia. Results: Seventeen studies including people with CHF (n ¼ 29,456) and 14 studies including people with COPD (n ¼ 23,116) were included. The pooled mean age for COPD was 66.3 years and for CHF, 75.6 years. The pooled prevalence of MCI in the COPD was 25% (95% CI: 23%, 42%) and ACI, 32% (95% CI: 18%, 38%). Correspondingly, the pooled prevalence of MCI in those with CHF was 32% (95% CI: 22%, 43%) and ACI, 31% (95% CI: 23%, 40%). Conclusions: One in 4 people with COPD and 1 in 3 people with CHF had MCI, respectively. The overall prevalence of ACI for COPD was 32% and for CHF, 31%. Future work should consider ways of detecting, managing, or improving cognitive function and other cognition-related outcomes in this group of people. Ó 2017 AMDA e The Society for Post-Acute and Long-Term Care Medicine.

Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) have great negative impact on the lives of older people, particularly in relation to quality of life, physical functioning, and increased utilization of health care resources.1,2 In addition, more than two-thirds of people with COPD3 and at least three-quarters of those with CHF4 are living with 1 or more additional chronic comorbidities that may have a further adverse effect on health outcomes, social The authors declare no conflicts of interest. * Address correspondence to Abebaw Mengistu Yohannes, PhD, MSc, FCCP, Professor of Respiratory Medicine and Gerontology, Manchester Metropolitan University, Department of Health Professions, Brooks Building, 53 Bonsall Street, Manchester M15 6GX, United Kingdom. E-mail address: [email protected] (A.M. Yohannes). http://dx.doi.org/10.1016/j.jamda.2017.01.014 1525-8610/Ó 2017 AMDA e The Society for Post-Acute and Long-Term Care Medicine.

interaction, dependence on family caregivers, health care utilization, and premature mortality.1e6 Furthermore, 1 in 5 people with COPD may develop CHF6; 1 in 3 people with CHF have unrecognized mild to moderate airways obstruction,7 and the overlap of symptoms/etiology may be a challenge to treat adequately when both conditions exist simultaneously. Furthermore, people with CHF and comorbid COPD display worse attention/executive function and poorer physical fitness level compared with their non-COPD counterparts.6e8 In general, cognitive impairment in those with chronic systemic conditions may compromise an individual’s ability to manage his or her own care and adhere to treatment. In 2010, a US study showed that people with COPD and CHF have similar rates of hospital readmission, at 36% and 37%, respectively.9 In

1.e2

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

addition, similar etiologic and behavioral factors, particularly cigarette smoking, are etiologic factors in the disease, and both conditions exhibit a similar range of symptoms and physical signs, including excessive dyspnea on exertion, and hypoxia. These symptoms may contribute collectively to increase the risk of cognitive impairment.6e9 Undetected cognitive impairment, as reflected by impaired performance in memory, language, visuospatial, and attention/executive tasks,10 may contribute to reduction in socially related activities, nonadherence to medical treatment, and heightened dependence on caregivers in patients with COPD and CHF.10e13 Cross-sectional studies have estimated the prevalence of cognitive impairment in general COPD at between 16% and 57%,14,15 and in CHF, it ranges from 13.5% to 80%.12,16 These wide variations in the estimated prevalence of cognitive impairment in both conditions might be due to the diversity of study designs, inclusion criteria, age range of participants, and the methods and neuropsychological assessment tools that have been used. Furthermore, the exact prevalence of the specific syndrome of “mild cognitive impairment” (MCI) in COPD and CHF is even less clear. Establishing an accurate epidemiology of this condition in chronic systemic diseases such as COPD and CHF is vital because MCI is a potential risk factor for increased disease burden in COPD and CHF, and further decreases in physical functioning and social interaction. Importantly, MCI and overall cognitive impairment may be a precursor to develop dementia in about a third of cases.17 It is possible that in the context of COPD/CHF, the proportion of those with MCI who progress to a full dementia syndrome may be greater

compared with a healthy cohort.18 To our knowledge, this question, though clinically important, has yet to be investigated. Nonetheless, greater insight into the prevalence of cognitive impairment in COPD and CHF is the first step toward a broader understanding of the impact of this condition on the lives of people with COPD and CHF, and the development of appropriate interventions. The types of interventions have to be individually tailored and involve a multidisciplinary team, particularly secondary careebased “memory services” and social support services. With this in mind, we have conducted a metaanalysis to determine the pool prevalence of MCI and cognitive impairment in CHF and COPD. This knowledge may encourage the more widespread screening for cognitive impairment, particularly in people or those with more advanced stages of COPD and CHF. Specifically, here we aim (1) to determine the prevalence of MCI and any cognitive impairment (ACI) in COPD and CHF and (2) to explore the consequences and clinical management of comorbid MCI and cognitive impairment in these 2 conditions. Methods Data Sources and Search Strategy Two experienced investigators independently searched for Cochrane Databases of systematic reviews, Embase databases (from January 1, 1980, to February 25, 2016) and Medline (1946 to present, including in-process and non-indexed citations) to identify primary

Identification

A Records iden fied through database searching (n = 198)

Addi onal records iden fied through other sources (n = 2 )

Screening

Records a er duplicates removed (n = 157)

Records screened (n = 157)

Included

Eligibility

Full-text ar cles assessed for eligibility (n = 17)

Records excluded (n = 140)

Full-text ar cles excluded, with reasons (n= 3) Cannot derive prevalence n=3

Studies included in quan ta ve synthesis (meta-analysis) (n = 14)

Fig. 1. (A) Cognitive impairment in COPD PRISMA1 Flow Diagram. (B) Cognitive impairment in CHF PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses.

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

studies related to prevalence of cognitive impairment in CHF and COPD. We used a search strategy combining text terms [“COPD” OR “chronic obstructive pulmonary disease,” “MCI” OR “mild cognitive impairment, cognitive impairment”] and [“CHF” OR “chronic heart failure,” “MCI” OR “mild cognitive impairment and cognitive impairment”]. We employed 2 independent searches simultaneously to extract the relevant articles for this review. Detailed search strategy and results are illustrated in Appendixes 1 and 2. A manual search was performed for the relevant references from the selected articles and published reviews. We first inspected the title and abstract to exclude inappropriate samples, outcomes, reports (eg, conference abstract), and nonextractable data, and then carefully examined the full text to identify appropriate studies per our inclusion and exclusion criteria. The inclusion criteria were as follows: (1) patients with COPD, (2) patients with CHF, (3) prevalence of MCI, and (4) prevalence of ACI. Studies that reported mean (standard deviation) of MCI and diagnosis of dementia were excluded. Figure 1A and B provide details of the inclusion and exclusion in the initial qualitative synthesis and subsequent meta-analysis. The final study pool included English-language peer-reviewed publications with CHF or COPD samples that reported a prevalence of cognitive impairment. Cognitive testing is optimal in objectively assessing the degree of cognitive impairment for an individual. The strict diagnosis involves a >1.5 to 2 standard deviation below the mean for their age-, gender- and education-matched peers on culturally appropriate normative data at least in 1 or more impaired

1.e3

cognitive domains typically including memory, and (for MCI) this must not impact significantly on functional ability.19 Data Extraction Two investigators (W.C. and A.M.) independently extracted study data and scrutinized for the eligibility of included studies. Disagreements were resolved by discussion or where necessary by arbitration by a third senior investigator (A.M.Y.), who also performed a crosscheck for data accuracy. We extracted data on study characteristics (study design, patient selection, number of patients) and patient characteristics (age; sex; COPD, CHF, and comorbidity status). We have also investigated factors that are associated with cognitive impairment in patients with COPD and CHF in the articles extracted for the meta-analyses. Data Analysis We performed meta-analyses to calculate the weighted-pooled summary estimates of prevalence of cognitive impairment in study samples with COPD and CHF, respectively. Before meta-analyses, we used the Freeman-Tukey double-arcsine transformation to normalize and variance-stabilize the distribution of proportions from included studies. After meta-analyses, we back-transformed the pooled estimates and corresponding 95% confidence intervals into proportions. The I2 values of 25%, 50%, and 75% are indicative of low, moderate, and high levels of heterogeneity (variance between studies),

Identification

B Records iden fied through database searching (n = 244)

Addi onal records iden fied through other sources (n = 5 )

Screening

Records a er duplicates removed (n = 199)

Records screened (n = 199)

Included

Eligibility

Full-text ar cles assessed for eligibility (n = 35)

Studies included in quan ta ve synthesis (meta-analysis) (n = 17)

Fig. 1. (continued).

Records excluded (n = 164)

Full-text ar cles excluded, with reasons (n= 18) Conference abstract n=2; Cannot derive prevalence n=14; Irrelevant studies (study with different endpoints) n=2

1.e4

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

accordingly.20 In the meta-analyses, we calculated random-effects pooled estimates to account for heterogeneity of reported proportions between different studies. Robustness of the metaprevalence estimates were examined using sensitivity analysis with a jackknife approach, where we repeated the meta-analysis multiple times, each time with the removal of an individual study from the overall pool of included studies. In this way, we can assess the impact of each single study on the overall pooled prevalence. In addition, we performed random effects meta-regression to identify the potential source of heterogeneity in pooled meta-prevalence, which used the same Freeman-Tukey double-arcsine transformation. The metaregression examined whether the age and gender distribution of the study samples explained variations in the prevalence of cognitive impairment. To detect the risk of publication bias and the small-study effect, we performed a funnel plot analysis by plotting the Freeman-Tukey double-arcsine transformed-prevalence estimates from individual

studies against their standard errors. The asymmetric inverted funnel shape suggests an association between pooled estimate and study size (publication or small study bias). The Egger test was also performed to objectively assess the funnel plot asymmetry, with publication bias indicated by a P value <.05. All analyses were performed using Stata 12.1 software package. For all analyses, significance was set at P < .05.

Results Our literature search and review of reference lists initially identified 200 articles for COPD and 249 articles for CHF. Figure 1A and B show the flowchart of study inclusion. Fourteen COPD studies (n ¼ 23,116 participants) and 17 CHF studies (n ¼ 29,456 participants) were selected for this review. Baseline characteristics for the included COPD and CHF study samples are shown in Tables 1 and 221e50 respectively.

Table 1 Sociodemographic Characteristics of COPD Patients Author (First), Year

Country

Design

Sample Size

Gender, % Female

Mean Age (SD) or Median (IQR)

Cognitive Assessment

% MCI

% ACI

OzyemisciTaskiran, 201521

Turkey

133 (COPD)

15

67.5 (8.9)

MMSE

22.6

N/A

Martinez, 201422

USA

15,723 (non-COPD) 1823 (COPD)

53.7 59.2

69.4 (10.4) 70.9 (9.4)

PBI

13.1 17.5

N/A

Singh, 201323

USA

1639 (non-COPD) 288 COPD

50 41.3

79.7 (75.2-83.6) 82.7 (79.2-85.8)

CDR

14.6 27.1

N/A

Dulohery, 201524

USA

100 (COPD)

37

MOCA

63

N/A

Dal Negro, 201425

Italy

Retrospective electronic medical record Population-based longitudinal study Population-based Mayo Clinic study of ageing Outpatient pulmonary clinic Outpatient pulmonary clinic

229 (COPD) 127 (CNOB) 46 (AS)

44.9 51.1 30.4

70.5 (12.9) 66.2 (15.7) 50.6 (11.3)

MMSE, CDT, TMT

32.8 15.7 0

Karamanli, 201526

Turkey

45 (COPD)

37.7

68.8 (12.1)

Dodd, 201527

UK

66.4 (6.2)

MMSE MOCA TMT

40 58 N/A

Chang, 201228

USA

Villeneuve, 201229

Canada

Incalzi, 200230

Italy

Outpatient pulmonary clinic Outpatient pulmonary clinic Population-based multicenter prospective study Outpatient pulmonary clinic Outpatient pulmonary clinic

CDT ¼ 16.6; TMT ¼ 44.2 CDT ¼ 8.7; TMT ¼ 28.3 CDT ¼ 0; TMT ¼ 2.2 None reported

Grant, 198231

USA

Incalzi, 200632

Italy

Thakur, 201033

USA

Schure, 201634

USA

Outpatient pulmonary clinic Outpatient pulmonary clinic prospective observational study Prospective longitudinal study Outpatient pulmonary clinic prospective observational study

2128 (COPD)

70 (9.4)

TMT ¼ 38

2519 (non-COPD) 431 (COPD)

59.8 48.7

Not reported

MMSE*

4.6 20.3

N/A

45 (COPD) 50 (Non-COPD) 233 (COPD) 203 (asthma) 92 (chronic bronchitis) 1080 (controls) 203 (COPD)

64.4 60.0 Not reported

68.4 (8.72) 67.4 (8.77) Age >64 y

MMSE

36.0 12.0 21.9 15.8 17.4 16.7

N/A

Not reported

65 (4.6)

N/A

42

134 (COPD)

16.4

68.7 (8.5)

32.8

MDB ¼ 10.4

1202 (COPD) 302 (non-COPD)

57.4 61.0

58.2 (6.2) 58.5 (6.2)

MMSE

5.5 2.0

N/A

68.4

TMT

301

8.5

MMSE

Neuropsychological test MMSE

N/A

29.2

AS, asymptomatic smokers; CDR, Clinical Dementia Rating scale; CDT, Clock Drawing Test; CNOB, chronic nonobstructive bronchitis; IQR, interquartile range; MDB, Mental Deterioration Battery; N/A, not applicable; PBI, performance-based instrument; SD, standard deviation; TMT, Trial Making Test. *MMSE (range 0-100). A 3MS score 1.5 SDs or before below the strata mean for race and educational level is highly specific for cognitive impairment. Lower 3MS score poorer cognitive function.

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

1.e5

Table 2 Sociodemographic Characteristics of CHF Patients Author (First), Year

Country

Design

Gathright, 201635

USA

Murad, 201536

USA

Prospective cohort at medical centers Population-based longitudinal study Cross-sectional sample at hospitals Prospective cohort at hospital heart clinics Cross-sectional outpatient setting Prospective cohort among hospitalized patients Multicenter, prospective cohort Cross-sectional at-home care service facilities

37

Kamrani, 2014

Pulignano, 2014

38

Iran Italy

Shaukat, 201439

USA

Dodson, 201340

Conn

Giallauria, 2013

41

Foebel, 201242

Italy Canada

Gure, 201243

USA

Hawkins, 2012

44

USA

Cameron, 201045

Australia

Halling, 200646

Sweden

McLennan, 2006

12

Australia

Akomolafe, 200547

USA

Zuccalà, 200548

Italy

Zuccalà, 2003

49

Italy

Zuccalà, 2001

50

Italy

Longitudinal administrative data sets Prospective cohort at a Veterans Administration facility Cross-sectional hospitalized sample Population-based, multicenter cohort Prospective cohort of hospital referrals Cross-sectional randomized controlled trial Retrospective hospital databases Retrospective hospital databases Retrospective hospital databases

Sample Size

Gender, % Female

Mean Age (SD) or Median (IQR)

Cognitive Assessment

% MCI

% ACI

302

37

68.7 (9.6)

MMSE

29.5

N/A

558

48

79.2 (6.3)

MMSE

17.0

N/A

184

61

60

AMT

NA

AMT<7: 59

190

46.30

MMSE

NA

MMSE <24: 38.9

182

NA

56.2 (16.0)

NA

282

53.2

80.0 (8.0)

Clinical diagnosis MMSE

25.20

46.8

285

34.00

71.3 (12.2)

MMSE

N/A

MMSE<¼21: 5.3

21,807

66.50

75-79: 18.6%; 80-84: 29.5%; 85þ: 51.9% 78.6 (6.86)

CPS

43.3

N/A

TICS-m

24

41.9

66.4 (9.8)

SLUMS

41.6

58.4

MOCA, MMSE

73

N/A

707 251

93

53 1.6

29

77 (5)

70 (11)

3.30

108

N/A

N/A

MMSE

N/A

MMSE <24: 44.4

200

40.7

80.7 (6.7)

MMSE

13.5

N/A

100

64

67.5 (9.0)

MMSE

N/A

MMSE <24: 10

1511

N/A

N/A

AMT

N/A

AMT <7: 35

1113

53.91

78.6

AMT

N/A

AMT <7: 32

1583

52.81

78.3

AMT

N/A

AMT < 7: 26

AMT, Iranian version of Abbreviated Mental Test; CPS, Cognitive Performance Scale; IQR, interquartile range; N/A, not applicable; PBI, performance-based instrument; PFT, pulmonary function test; SD, standard deviation; SLUMS, Saint Louis University Mental Status examination; TICS-m: a modified version of the Telephone Interview for Cognitive Status.

COPD

CHF

Figure 2 shows the 14 data sets from 14 unique studies based on the COPD samples that were included in the meta-analysis. The pooled mean age was 66.3 years (95% CI: 61.9, 70.8), and the pooled prevalence of female participants was 37% (95% CI: 27%, 47%). The pooled prevalence of overall ACI was 32% (95% CI: 23%, 42%). Eleven articles that specifically reported the prevalence of the syndrome “MCI” had a pooled prevalence of MCI of 25% (95% CI: 0.17%, 0.35%). Results of the jackknife sensitivity analysis are shown in Table 3. The pooled prevalence of overall ACI ranged between 23% and 42% when the meta-analysis was repeated, with each included study being excluded one at a time. In particular, the inclusion of the study by Dulohery et al24 increased the pooled prevalence MCI from 22% to 25%. This was partly due to the relatively small sample size (n ¼ 100), and that nearly two-thirds of the participants were male and recruited from outpatient clinics. In the meta-regressions, age and gender were unable to explain between-study variations in the prevalence of cognitive impairment in COPD (P values of .076 and .191, respectively). In the funnel plot analysis, the transformed prevalence estimates from different studies were generally symmetrically distributed, suggesting no systematic difference between small and large studies (Egger test P ¼ .46, Figure 3A with cognitive impairment; and Egger test P ¼ .55, Figure 3C, with MCI, accordingly).

Figure 4 shows 17 data sets from 17 unique studies with reported prevalence of cognitive impairment in CHF. The pooled mean age was 75.6 years (95% CI: 71.5, 79.8), and the pooled prevalence of female participants was 42% (95% CI: 33%, 52%). The pooled prevalence of overall ACI was estimated at 30% (95% CI: 25%, 45%), with 8 studies reporting the prevalence of MCI specifically pooled prevalence: 32% (95% CI: 22%, 43%). In the jackknife sensitivity analysis in Table 4, the pooled prevalence remained stable, ranging from 26% to 43%. Cameron et al45 published one of the most influential studies that elevated the overall pooled prevalence from 25% to 29%. In this study, 71% of the sample was male and the sample size was relatively small (n ¼ 93) and was recruited from outpatient clinics. In the meta-regressions, neither age nor gender could explain heterogeneity in MCI and CI prevalence in CHF patients (CI: age P ¼ .48, gender P ¼ .62; MCI: age P ¼ .09, gender P ¼ .45). However, in the funnel plot analysis (Egger test P < .05), small studies systematically reported higher prevalence in MCI than large studies in CHF (Figure 3D), with no systematic difference between small and large studies in ACI (Egger test P ¼ .81, Figure 3B). Cognitive Assessment Tools In the 14 COPD studies included for analysis, the following assessment tools or diagnostic criteria were used to identify MCI: the

1.e6

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

Fig. 2. Meta-analysis for studies with cognitive impairment and MCI in patients with COPD.

Mini Mental State Examination (MMSE; n ¼ 8; 53%), the Montreal Cognitive Assessment (MOCA; n ¼ 2; 14%), a nonspecific “neuropsychological test” (n ¼ 2; 14%), and a “performance-based instrument” (n ¼ 2; 14%). In the 17 CHF studies included for analysis, the following assessment tools or diagnostic criteria were used to identify MCI: MMSE

(n ¼ 9; 53%), the Abbreviated Mental Test (n ¼ 4; 24%), the MOCA (n ¼ 2; 14%), a nonspecific “neuropsychological test” (n ¼ 1; 7%), and a “performance-based instrument” (n ¼ 1; 7%). Appendixes 3 and 4 show sociodemographic characteristics, comorbidities, and clinical characteristics that are associated to cognitive impairment in patients with COPD and CHF.

Table 3 The Jackknife Sensitivity Analysis of Pooled Prevalence of ACI and MCI in Patients With COPD

Discussion

Prevalence in Single Study (95% CI) ACI Dal Negro, 201425 Dodd, 201527 Grant, 198231 Incalzi, 200632 Schure, 201634 MCI Chang, 201228 Dal Negro, 201425 Dulohery, 201524 Incalzi, 200230 Incalzi, 200632 Karamanli, 201526 Martinez, 201422 Ozyemisci-Taskiran, 201521 Singh, 201323 Thakur, 201033 Villeneuve, 201229

0.32 0.44 0.38 0.42 0.1 0.29 0.25 0.05 0.33 0.63 0.22 0.33 0.4 0.17 0.23

(0.23, (0.38, (0.36, (0.35, (0.06, (0.24, (0.17, (0.03, (0.27, (0.53, (0.17, (0.25, (0.27, (0.16, (0.16,

0.42) 0.51) 0.4) 0.49) 0.17) 0.35) 0.35) 0.07) 0.39) 0.72) 0.28) 0.41) 0.55) 0.19) 0.3)

0.27 (0.22, 0.32) 0.05 (0.04, 0.07) 0.36 (0.23, 0.5)

Meta-prevalence (95% CI) When Study was Excluded

Weight (%)

0.29 0.3 0.3 0.38 0.33

(0.19, (0.17, (0.19, (0.33, (0.22,

0.41) 0.45) 0.42) 0.43) 0.45)

19.86 21.49 19.85 18.74 20.27

0.28 0.25 0.22 0.26 0.25 0.24 0.26 0.26

(0.19, (0.16, (0.14, (0.16, (0.16, (0.15, (0.15, (0.16,

0.38) 0.34) 0.3) 0.36) 0.35) 0.34) 0.39) 0.36)

9.47 9.31 8.9 9.32 9.08 8.13 9.61 9.08

0.25 (0.16, 0.35) 0.28 (0.19, 0.38) 0.24 (0.16, 0.34)

9.38 9.59 8.13

To our knowledge, this is the first systematic review and metaanalysis to investigate the prevalence of MCI in pooled data from studies of populations of people with COPD or CHF in both a mixed clinical hospital-based and home-based population. Our findings revealed that (1) approximately 1 in 4 people with COPD and 1 in 3 people with CHF are reported as having MCI; (2) the overall prevalence of ACI in people with COPD and CHF was 32% and 30%, respectively; and (3) the MMSE was the preferred tool used in assessing cognitive impairment in both COPD and CHF. What Are the Implications of Our Findings to Clinical Practice? First, our findings indicate that the prevalence of MCI is far higher in COPD (25%) and CHF (35%) compared to the prevalence of MCI in the general population, which is in the range of 10% to 20% in older adults.51 Nevertheless, the exact cause(s) and mechanism of pathogenesis by which CHF and COPD population tend to manifest a high prevalence of cognitive impairment is uncertain. Two recent studies52,53 have reported that COPD and CHF populations exhibit high prevalence of cerebrovascular diseases that in turn may expose individuals to impaired brain perfusion due to chronic hypoxia and

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

1.e7

Fig. 3. Funnel plot analysis with Egger test for distribution asymmetry of prevalence estimates. (A) COPD with ACI prevalence. (B) CHF with ACI prevalence. (C) COPD with MCI prevalence. (D) CHF with MCI prevalence.

“facilitate” cognitive impairment. It is reasonable to assume patients with COPD and CHF are at an amplified risk of neuronal injury through factors related to COPD and CHF such as hypoxemia and/or because of comorbidities that adversely affect the brain, such as vascular disease and smoking.11 Given that those with MCI, particularly the amnestic form, have a high risk of progression to dementia, it is very likely that in the context of COPD and CHF, the risk may be even higher because of the high prevalence of cardiovascular disease such as stroke and hypertension52,53 and cerebrovascular disease (eg, active smokers) and higher pathologic load on the brain, shortening the trajectory of conversion from MCI to dementia. Furthermore, hypoxia may predispose to dysfunction of the hippocampal neurons to increase the risk of cognitive impairment by reduction in size and volume of the hippocampus and brain atrophy.11,54 Another critical point is that overall morbidity and disease burden of the individuals may be substantially higher than in those with single or less complex conditions. We speculate that hypoxemia might be a common drive to the development of cognitive impairment in patients with moderate to severe COPD and CHF. It could be comorbidities that influence impairment in executive tasks requiring memory and attention allocation, and these factors could potentially explain the relationship between cognitive impairment in patients with COPD and CHF. Furthermore, cognitive impairment may contribute to increased behavioral disturbances (eg, panic and

anxiety/depression) and poor adherence to rehabilitation and drug therapy, which are much higher in COPD and CHF55 than in patients with other conditions.56,57 In addition, the increased risk for cognitive impairment in patients with COPD and CHF shown in our data may be partially explained by the potential role of inflammation and vascular disease in pathogenesis of MCI and cognitive impairment. Recent studies reported that patients with CHF and COPD have increased levels of systemic inflammatory markers such C-reactive protein, interleukin 6, and fibrinogen.58,59 These inflammatory markers have been associated with MCI in other chronic conditions including diabetes60 and stroke.61 Indeed, COPD severity is associated with an amplified risk for cardiovascular disease,62 and cardiovascular disease is a risk factor MCI.63 Furthermore, a recent64 large-scale study of the Taiwanese National Health Insurance Research Database (n ¼ 20,492) showed that COPD increased the risk of developing dementia (1.27, 95% confidence interval 1.20-1.36) compared to non-COPD patients, and in turn dementia increased the risk of inpatient hospital mortality (1.69, 95% confidence interval 1.18-2.43) from COPD.65 Undetected and untreated MCI and overall ACI may have an adverse impact on patients’ quality of life and physical activity (and thus independence) and potentially adherence to medical treatment and rehabilitation. There is often an ignored substantial disease burden of MCI that results in dependence and distress on family

1.e8

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

Fig. 4. Meta-analysis for studies with ACI and MCI in patients with CHF.

Table 4 The Jackknife Sensitivity Analysis of Pooled Prevalence of ACI and MCI in Patients with CHF Prevalence in Single Study (95% CI) ACI Akomolafe, 200547 Dodson, 201340 Giallauria, 201341 Gure, 201243 Halling, 200646 Hawkins, 201244 Kamrani, 201437 Pulignano, 201438 Shaukat, 201439 Zuccalà, 200150 Zuccalà, 200349 Zuccalà, 200548 MCI Cameron, 201045 Dodson, 201340 Foebel, 201242 Gathright, 201535 Gure, 201243 Hawkins, 201244 McLennan, 200612 Murad, 201536

0.31 0.10 0.47 0.05 0.42 0.44 0.59 0.59 0.39 0.03 0.26 0.32 0.35 0.32 0.73 0.25 0.43 0.29 0.24 0.41 0.14 0.17

(0.23, 0.40) (0.06, 0.17) (0.41, 0.53) (0.03, 0.09) (0.38, 0.46) (0.35, 0.54) (0.52, 0.64) (0.52, 0.66) (0.32, 0.46) (0.02, 0.07) (0.24, 0.28) (0.29, 0.35) (0.33, 0.37) (0.22, 0.43) (0.63, 0.81) (0.2, 0.31) (0.43, 0.44) (0.25, 0.35) (0.21, 0.27) (0.36, 0.48) (0.09, 0.19) (0.14, 0.2)

Meta-prevalence (95% CI) When Study was Excluded

Weight (%)

0.34 0.3 0.35 0.3 0.3 0.29 0.29 0.31 0.35 0.32 0.31 0.31

(0.25, (0.22, (0.27, (0.22, (0.22, (0.21, (0.21, (0.22, (0.27, (0.23, (0.22, (0.22,

0.42) 0.39) 0.42) 0.4) 0.39) 0.38) 0.38) 0.4) 0.43) 0.42) 0.41) 0.41)

7.87 8.38 8.38 8.56 7.93 8.34 8.22 8.24 8.22 8.63 8.60 8.63

0.27 0.33 0.31 0.33 0.34 0.31 0.35 0.35

(0.17, 0.38) (0.22, 0.45) (0.21, 0.41) (0.21, 0.45) (0.22, 0.46) (0.2, 0.43) (0.25, 0.46) (0.25, 0.45)

11.72 12.51 12.94 12.54 12.77 12.46 12.34 12.72

caregivers (including the need to cope with behavioral changes of the patients with COPD and CHF). There was no significant relationship between the pooled prevalence of mean age and gender with the high prevalence of MCI in both CHF and COPD patients. The reason(s) for the lack of relationship is unclear. It is possible that the cognitive performance declines in the observed studies were “point of prevalence in MCI” rather than observed in repeated measures follow-up. It simply reflects that cognitive impairment may be persistent and less salient for clinicians to recognize in patients with COPD and CHF in the presence of hypoxemia. Thus, our finding is novel and highlights the relevance of screening patients with COPD and CHF for cognitive assessment during diagnoses of these diseases, and of periodically monitoring cognitive status in routine clinical follow-up. In addition, a recent study showed that cognitive impairment was associated with an increased 30-day hospital admission rate in patients with CHF.66 Further prospective research is warranted to examine the onset and progression of MCI in patients with CHF and COPD. None of the reviewed studies has reported the efficacy of interventions in the treatment of MCI in COPD and CHF patients. Thus, it is important for health care professionals to pay special attention and be vigilant where appropriate when COPD and/or CHF patients verbalize their forgetfulness and/or poor adherence to medical treatment. These subtle “flags” should prompt clinicians to conduct further assessment using a screening tool (eg, MMSE and MOCA to

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

assess for MCI) and monitoring of patients’ cognitive status. Those identified with a screening tool as possibly having MCI should be referred for further assessment to memory clinics by a psychiatrist or a psychologist. However, the lack of sensitivity of the MMSE to detect MCI, particularly if there is more executive dysfunction rather than memory problems, suggests the need for a better tool. For example, the MOCA, which has validated cut-offs for MCI, has a broader score range and less ceiling effect,67,68 more items to test executive function, and is a short, screening tool practical to use in acute hospital settings by nonspecialists. Furthermore, in the majority of cases, the clinical and sociodemographic characteristics and comorbidities that are associated with cognitive impairment in both conditions were similar in Appendixes 3 and 4. The strength of our study is its robust statistical analyses to provide concrete estimates for the prevalence of MCI that can guide health care professionals with “real-world scenarios” to improve care for patients with COPD and CHF. Our study has several limitations, however. First, we pooled data from a large number of studies, and this may have introduced bias because of differences in the methods used for cognitive assessment, cut-off definition, participant selection, and other aspects of study design. However, we performed a jackknife sensitivity analysis for both COPD and CHF and showed that the pooled prevalence of overall cognitive impairments is generally stable regardless of heterogeneity across different studies (Tables 3 and 4). Second, the diagnostic tools that have been used in various studies were screening tools with different levels of cut-off points. Thus, the diagnosis of MCI and overall cognitive impairment reported in individual studies were not always apparent. None of the studies had used interviews based on the Diagnostic and Statistical Manual of Mental Disorders as the gold standard to validate their findings. Thus, further work is needed. Third, we have attempted to minimize publication bias through searching for gray literature and unpublished work but the pooled prevalence estimate of cognitive impairment in CHF was still affected by publication bias. Fourth, there are a number of weaknesses in this meta-analysis, including small sample sizes, data-based and retrospective studies, setting up of the studies in outpatient clinics, and population-based studies. Thus, caution is required in interpretation of our findings, especially the unpooled prevalence estimates for ACI for COPD ranging from 6.3% to 63.2% and for CHF ranging from 5.0% to 59%, respectively. These elevated rates of cognitive impairment in patients with COPD and CHF might be due to cognitive assessment tools that have been used in various studies and countries. These differences illustrate whether a cognitive assessment tool that has been developed in one country may be judiciously applied to another country despite going through cultural adaptation and language translations. Furthermore, we used published data for our meta-analysis; therefore, undesired publication bias was inexorable. Finally, we did not explore potential confounders, for example, anxiety, depression, obstructive sleep apnea, and dyspnea, which are highly prevalent in patients with COPD and CHF and their potential contribution to cognitive impairment. Furthermore, structural brain changes and executive dysfunction are common in CHF patients and may attribute to the deleterious effects of depression and poor autonomic functioning.69 Studies are needed to examine whether treating depression improves cognitive functioning in CHF patients. In summary, our findings showed that MCI and poorer cognitive performances are common in patients with COPD and CHF. Thus, we would argue that routine screening for decline in cognitive performance in both CHF and COPD are necessary in order to detect and treat appropriately and to improve concurrent management of both conditions. Prospective large randomized controlled trials are needed to examine the efficacy of interventions to elucidate the impact of cognitive impairment.

1.e9

References 1. Parshall MB, Schwartzstein RM, Adams L, et al. on behalf of the ATS Committee on Dyspnea. An official American Thoracic Society Statement: Update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012;185:435e452. 2. Jhund PS, Macintyre K, Simpson CR, et al. Long-term trends in first hospitalization for heart failure and subsequent survival between 1986 and 2003: A population study of 5.1 million people. Circulation 2009;119:515e523. 3. Sode BF, Dahl M, Nordestgaard BG. Myocardial infarction and other comorbidities with chronic obstructive pulmonary disease: A Danish Nationwide study of 7.4 million individuals. Eur Heart J 2011;32:2365e2375. 4. Maggoni AP, Anker SD, Dahlstrom UL, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173e1184. 5. Doos L, Uttley J, Onyia I, et al. Mosaic segmentation, COPD and CHF multimorbidity and hospital admission costs: A clinical linkage study. J Public Health (Oxf) 2014;36:317e324. 6. Hawkins NM, Jhund PS, Simpson CR, et al. Primary care burden and treatment of patients with heart failure and chronic obstructive pulmonary disease in Scotland. Eur J Heart Fail 2010;12:17e24. 7. Macchia A, Rodriguez Moncalvo JJ, Kleinert M, et al. Unrecognised ventricular dysfunction in COPD. Eur Respir J 2012;39:51e58. 8. Alosco ML, Spitznagel MB, Josephson R, et al. COPD is associated with cognitive dysfunction and poor physical fitness in heart failure. Heart Lung 2015;44: 21e26. 9. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med 2009;360:1418e1428 [Erratum: N Engl J Med 2011;364:1582]. 10. Li J, Fei GH. The unique alterations of hippocampus and cognitive impairment in chronic obstructive pulmonary disease. Respir Res 2013;14:140. 11. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Resp J 2013;35: 913e922. 12. McLennan SN, Pearson SA, Cameron J, Stewart S. Prognostic importance of cognitive impairment in chronic heart failure patients: Does specialist management make a difference? Eur J Heart Fail 2006;8:494e501. 13. Yohannes AM. Cognitive impairment and risk of disability in chronic obstructive pulmonary disease. Ann Am Thorac Soc 2014;11:1445e1446. 14. Singh B, Mielke MM, Parsaik AK, et al. A prospective study of chronic obstructive pulmonary disease and risk of mild cognitive impairment. JAMA Neurol 2014;71:581e588. 15. Dodd JW, Charlton RA, van den Broek MD, Jones PW. Cognitive dysfunction in patients hospitalized with acute exacerbation of COPD. Chest 2013;144: 119e127. 16. Levin SN, Hajduk AM, McManus DD, et al. Cognitive status in patients hospitalized with acute decompensated heart failure. Am Heart J 2014;168: 917e923. 17. Ma F, Wu T, Miao R, et al. Conversion of mild cognitive impairment to dementia among subjects with diabetes: A population-based study of incidence and risk factors with five years of follow-up. J Alzheimers Dis 2015;43:1441e1449. 18. Marcos G, Santabárbara J, Lopez-Anton R, et al. ZARADEMP Workgroup. Conversion to dementia in mild cognitive impairment diagnosed with DSM-5 criteria and with Petersen’s criteria. Acta Psychiatr Scand 2016;133:378e385. 19. Albert MS, Dekosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on ageing and Alzheimer’s association group. Alzheimers Dement 2011;7:270e279. 20. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557e560. 21. Ozyemisci-Taskiran O, Bozkurt SO, Kokturk N, Karatas GK. Is there any association between cognitive status and functional capacity during exacerbation of chronic obstructive pulmonary disease? Chron Respir Dis 2015;12: 247e255. 22. Martinez CH, Richardson CR, Han MK, Cigolle CT. Chronic obstructive pulmonary disease, cognitive impairment, and development of disability: The Health and Retirement Study. Ann Am Thorac Soc 2014;11:1362e1370. 23. Singh B, Parsaik AK, Mielke MM, et al. Chronic obstructive pulmonary disease and association with mild cognitive impairment: The Mayo Clinic Study of Aging. Mayo Clin Proc 2013;88:1222e1230. 24. Dulohery MM, Schroeder DR, Benzo RP. Cognitive function and living situation in COPD: Is there a relationship with self-management and quality of life? Int J Chron Obstruct Pulmon Dis 2015;10:1883e1889. 25. Dal Negro RW, Bonadiman L, Tognella S, et al. Extent and prevalence of cognitive dysfunction in chronic obstructive pulmonary disease, chronic nonobstructive bronchitis, and in asymptomatic smokers, compared to normal reference values. Int J Chron Obstruct Pulmon Dis 2014;9:675e683. 26. Karamanli H, Ilik F, Kayhan F, Pazarli AC. Assessment of cognitive impairment in long-term oxygen therapy-dependent COPD patients. Int J Chron Obstruct Pulmon Dis 2015;10:2087e2094. 27. Dodd JW, Novotny P, Sciurba FC, Benzo RP. NETT Research Group. Executive function, survival, and hospitalization in chronic obstructive pulmonary disease. A longitudinal analysis of the National Emphysema Treatment Trial (NETT). Ann Am Thorac Soc 2015;12:1473e1481.

1.e10

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

28. Chang SS, Chen S, McAvay GJ, Tinetti ME. Effect of coexisting chronic obstructive pulmonary disease and cognitive impairment on health outcomes in older adults. J Am Geriatr Soc 2012;60:1839e1846. 29. Villeneuve S, Pepin V, Rahayel S, et al. Mild cognitive impairment in moderate to severe COPD: A preliminary study. Chest 2012;142:1516e1523. 30. Incalzil RA, Bellia V, Maggi S, et al. Salute Respiratoria nell’ Anziano Study Group. Mild to moderate chronic airways disease does not carry an excess risk of cognitive dysfunction. Aging Clin Exp Res 2002;14:395e401. 31. Grant I, Heaton RK, McSweeny AJ, et al. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med 1982;142: 1470e1476. 32. Incalzi AR, Corsonello A, Pedone C, et al. Drawing impairment predicts mortality in severe COPD. Chest 2006;130:1687e1694. 33. Thakur N, Blanc PD, Julian LJ, et al. COPD and cognitive impairment: The role of hypoxemia and oxygen therapy. Int J Chron Obstruct Pulmon Dis 2010;5: 263e269. 34. Schure MB, Borson S, Nguyen HQ, et al. Associations of cognition with physical functioning and health-related quality of life among COPD patients. Respir Med 2016;114:46e52. 35. Gathright EC, Fulcher MJ, Dolansky MA, et al. Cognitive function does not impact self-reported health-related quality of life in heart failure patients. J Cardiovasc Nurs 2016;31:405e411. 36. Murad K, Goff DC Jr, Morgan TM, et al. Burden of comorbidities and functional and cognitive impairments in elderly patients at the initial diagnosis of heart failure and their impact on total mortality: The Cardiovascular Health Study. JACC Heart Fail 2015;3:542e550. 37. Kamrani AA, Foroughan M, Taraghi Z, et al. Self care behaviors among elderly with chronic heart failure and related factors. Pak J Biol Sci 2014;17: 1161e1169. 38. Pulignano G, Del Sindaco D, Di Lenarda A, et al. Chronic renal dysfunction and anaemia are associated with cognitive impairment in older patients with heart failure. J Cardiovasc Med (Hagerstown) 2014;15:481e490. 39. Shaukat A, Habib A, Lane KA, et al. Anticholinergic medications: An additional contributor to cognitive impairment in the heart failure population? Drugs Aging 2014;31:749e754. 40. Dodson JA, Truong TT, Towle VR, et al. Cognitive impairment in older adults with heart failure: Prevalence, documentation, and impact on outcomes. Am J Med 2013;126:120e126. 41. Giallauria F, Fattirolli F, Tramarin R, et al. Cardiac rehabilitation in chronic heart failure: Data from the Italian SurveY on carDiac rEhabilitation (ISYDE-2008). J Cardiovasc Med (Hagerstown) 2014;15:155e163. 42. Foebel AD, Hirdes JP, Heckman GA. Caregiver status affects medication adherence among older home care clients with heart failure. Aging Clin Exp Res 2012;24:718e721. 43. Gure TR, Blaum CS, Giordani B, et al. Prevalence of cognitive impairment in older adults with heart failure. J Am Geriatr Soc 2012;60:1724e1729. 44. Hawkins LA, Kilian S, Firek A, et al. Cognitive impairment and medication adherence in outpatients with heart failure. Heart Lung 2012;41:572e582. 45. Cameron J, Worrall-Carter L, Page K, et al. Does cognitive impairment predict poor self-care in patients with heart failure? Eur J Heart Fail 2010;12:508e515. 46. Halling A, Berglund J. Association of diagnosis of ischaemic heart disease, diabetes mellitus and heart failure with cognitive function in the elderly population. Eur J Gen Pract 2006;12:114e119. 47. Akomolafe A, Quarshie A, Jackson P, et al. The prevalence of cognitive impairment among African-American patients with congestive heart failure. J Natl Med Assoc 2005;97:689e694. 48. Zuccalà G, Marzetti E, Cesari M, et al. Correlates of cognitive impairment among patients with heart failure: Results of a multicenter survey. Am J Med 2005; 118:496e502. 49. Zuccalà G, Pedone C, Cesari M, et al. The effects of cognitive impairment on mortality among hospitalized patients with heart failure. Am J Med 2003;115:97e103.

50. Zuccalà G, Onder G, Pedone C, et al. Hypotension and cognitive impairment: Selective association in patients with heart failure. Neurology 2001;57:1986e1992. 51. Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment. A clinical review. JAMA 2014;32:2551e2561. 52. Black-Shinn JL, Kinney GL, Wise AL, et al. COPDGene Investigators. Cardiovascular disease is associated with COPD severity and reduced functional status and quality of life. COPD 2014;11:546e551. 53. Roberts RO, Geda YE, Knopman DS, et al. Cardiac disease associated with increased risk of nonamnestic cognitive impairment: Stronger effect on women. JAMA Neurol 2013;70:374e382. 54. Kalaria RN. Cerebrovascular disease and mechanisms of cognitive impairment. Evidence from clinicopathological studies in human. Stroke 2012;43: 2526e2534. 55. Fan VS, Meek PM. Anxiety, depression and cognitive impairment in patients with chronic respiratory disease. Clin Chest Med 2014;35:399e409. 56. Lyketsos CG, Toone L, Tschanz J, et al. Cache County Study Group. Populationbased study of medical comorbidity in early dementia and “cognitive impairment, no dementia (CIND)”: Association with functional and cognitive impairment: The Cache County Study. Am J Geriatr Psychiatry 2005;13: 656e664. 57. Hayden KM, Zandi PP, Lyketsos CG, et al. Cache County Investigators. Vascular risk factors for incident Alzheimer disease and vascular dementia: The Cache County study. Alzheimer Dis Assoc Disord 2006;20:93e100. 58. Rajendiran KS, Ananthanarayanan RH, Satheesh S, Rajappa M. Elevated levels of serum sialic acid and high-sensitivity C-reactive protein: Markers of systemic inflammation in patients with chronic heart failure. Br J Biomed Sci 2014;71:29e32. 59. Su B, Liu T, Fan H, et al. Inflammatory markers and the risk of chronic obstructive pulmonary disease: A systematic review and meta-analysis. PLoS One 2016;11:e0150586. 60. Gorska-Ciebiada M, Saryusz-Wolska M, Borkowska A, et al. Serum levels of inflammatory markers in depressed elderly patients with diabetes and mild cognitive impairment. PLoS One 2015;10:e0120433. 61. Narasimhalu K, Lee J, Leong YL, et al. Inflammatory markers and their association with post stroke cognitive decline. Int J Stroke 2015;10:513e518. 62. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008; 32:962e969. 63. Knopman DS, Roberts RO, Geda YE, et al. Association of prior stroke with cognitive function and cognitive impairment: A population-based study. Arch Neurol 2009;66:614e619. 64. Liao WC, Lin CL, Chang SN, et al. The association between chronic obstructive pulmonary disease and dementia: A population-based retrospective cohort study. Eur J Neurol 2015;22:334e340. 65. Liao KM, Lin TC, Li CY, Yang YH. Dementia increases sepsis and mortality in hospitalized patients with chronic obstructive pulmonary disease. Medicine (Baltimore) 2015;94:e967. 66. Agarwal KS, Kazim R, Borson S, Taffet GE. Unrecognized cognitive impairment and its effect on heart failure readmissions of elderly adults. J Am Geriatr Soc 2016;64:2296e2301. 67. Trzepacz PT, Hochstetler H, Wang S, et al. Alzheimer’s Disease Neuroimaging Initiative. Relationship between the Montreal Cognitive Assessment and Minimental State Examination for assessment of mild cognitive impairment in older adults. BMC Geriatr 2015;15:107. 68. Cameron J, Worrall-Carter L, Page K, et al. Screening for mild cognitive impairment in patients with heart failure: Montreal Cognitive Assessment versus Mini Mental State Exam. Eur J Cardiovasc Nurs 2013;12: 252e260. 69. Gathright EC, Walter FA, Hawkins MA, et al. Executive function moderates the relationship between depressive symptoms and resting heart rate variability in heart failure. J Behav Med 2016;39:192e200.

A.M. Yohannes et al. / JAMDA xxx (2017) 1.e1e1.e11

Appendix 1. Search Strategy: CHF Databases: Embase 1980 to 2016 February 22, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) 1946 to Present. 1 2 3 4 5 6 7 8 9

Heart Failure/< 251797 Cognitive impairment.tw.< 84330 and/1-2<721 Co-morbidity/ or Comorbidity/ or Co-morbidity/<225380 prevalence.tw.<1002555 or/4-5<1194906 and/3,6<263 limit 7 to yr ¼ “2000-current”<259 limit 8 to english<244

Co-morbidities/

or

10 remove duplicates from 9<196

Appendix 2. Search Strategy: COPD Databases: Embase 1980 to 2016 February 22, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) 1946 to Present 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

chronic obstructive pulmonary disease or COPD/< 109499 chronic obstructive lung disease.mp.< 88587 or/1-2< 146273 Cognitive impairment.mp.< 89664 and/3-4< 474 Co-morbidity/ or Comorbidity/ or Co-morbidities/ or Comorbidity/< 354391 prevalence.tw.< 1211173 or/6-7< 1501704 and/5,8< 227 limit 9 to yr ¼ “2000-current”< 216 limit 10 to english< 198 remove duplicates from 11< 155

1.e11

Appendix 3. Common Sociodemographic Characteristics, Clinical Symptoms, and Comorbidities With Reported Association Between Patients With COPD and Cognitive Impairment

Sociodemographic characteristics Older age23,24,26,30,32 Female gender30 Male gender23,30 Lower social class status27,30 Active smoking status27,30 Lower level of education23,24,27,29,30 Clinical characteristics and symptoms Decreased grip strength34 Decreased exercise tolerance21,27,30,32,34 Increased dyspnea21,34 Frequent acute exacerbations21 Frequent hospitalizations26,28 Increased prevalence rate of death28,32 Higher prevalence of falls history26 Increased level of hypoxemia25,32 Decreased independence in activities of daily living30 Increased use of long-term oxygen therapy27 Increased level of PaCO227 Decreased level of oxygen saturation33 Decrease in percentage of forced expiratory volume in 1 second30 Increased clock drawing test impairment25,32 Poorer quality of life25,27,34 Comorbidities Vascular comorbidities, eg, stroke, coronary artery disease, hypertension23,25,29 Higher prevalence of depression21,23,27

Appendix 4. Common Sociodemographic Characteristics, Clinical Symptoms, and Comorbidities With Reported Association Between Patients With CHF and Cognitive Impairment

Sociodemographic Lower level of education12,48,50 Lower social status44 Older age12,44,45,47e50 Female gender49 Male gender50 African American race44 Clinical characteristics and symptoms Poorer quality of life50 Frequent hospitalizations12,40 Increased prevalence rate of death12,36,49 Higher prevalence of depression44,45,49 Lower systolic blood pressure50 Greater comorbidity36,37,48,50 Hyperglycemia48 Low serum albumin48 Low sodium levels37,48 Low potassium levels48 Polypharmacy37 Hearing impairment37 Visual impairment37 Anticholinergic medication39 Premature mortality40,41 Nonadherence to medication42,44 Comorbidities COPD50 Anemia48,50 Chronic kidney disease50 vascular comorbidities, eg, stroke, coronary artery disease, hypertension43,50