A Multicenter Study of COPD and Cognitive Impairment: Unraveling the Interplay of Quantitative CT, Lung Function, HIF-1α, and Clinical Variables

Figures & data

Figure 1 QCT evaluation using 3D slicer software. (A and B) Density evaluation based on %LAA₋₉₅₀ after lung segmentation to define emphysema. (C) Airway evaluation in the third generation of the right lung resulting in %WA. (D) An HRCT axial view, mediastinum window to measure PA:A ratio and (E) Measurement PMA and PMD on the level right above the aortic arch showing pectoralis muscle segmentation (bright red = major pectoralis muscle; brownish red = minor pectoralis muscle).

Abbreviations: QCT, quantitative CT scan; HRCT, high-resolution CT scan; %LAA₋₉₅₀, percentage of lung attenuation area <−950 HU; %WA, wall area percentage; PA:A ratio, pulmonary artery-to-aorta ratio; PMA, pectoralis muscle area; PMD, pectoralis muscle density.

Table 1 Participants’ Characteristics

Parameters	GOLD				p-value
	GOLD I (n = 16)	GOLD II (n = 39)	GOLD III (n = 43)	GOLD IV (n = 16)
Quantitative CT
%LAA−950, %	29.1 ± 8.2	29.5 ± 8.7	35.4 ± 8.5	40.98 ±8.2	<0.001*
%WA, %	70.0 ± 5.9	68.9 ± 9.96	69.5 ± 7.69	68.57 ±7.97	0.952
PA:A ratio	0.8 ± 0.2	0.8 ± 0.2	0.86 ± 0.2	0.88 ± 0.2	0.195
PMA, mm^2	731.9 ± 211.4	732.8 ± 358.9	720.8 ± 393.5	647.1 ± 156.3	0.846
PMD, HU	38.7 ± 9.8	35.4 ± 11.4	35.8 ± 7.8	36.2 ± 10.4	0.707
Clinical
Age (</≥ 60 years)^a	3/13	13/26	10/33	11/5	0.005*
Education duration, years	12.6 ± 4.2	11.3 ± 3.3	10.9 ± 4.2	11.3 ± 3.7	0.489
COPD duration (</≥ 5 years)^a	6/10	27/12	20/23	13/3	0.014*
BMI, kg/m^2	25.5 ± 4.9	23.0 ± 4.8	21.1 ± 4.1	20.6 ± 3.8	0.003*
Brinkman index (cigarettes-year)	583.8 ± 634.1	603.5 ± 604.3	801.5 ± 820.4	680 ± 570.3	0.556
MoCA-Ina score	23.56 ± 4.0	23.26 ± 4.1	22.40 ± 3.8	22.06 ± 4.6	0.564
FEV1pp, %	91.6 ± 10.8	62.6 ± 10.6	39.3 ± 6.2	23.8 ± 5.5	<0.001*
FEV1/FVC, %	64.7 ± 4.7	56.7 ± 7.9	46.7 ± 10.3	36.5 ± 7.4	<0.001*
HIF-1α (pg/mL)	126.3 ± 3.0	51.2 ± 12.2	56.4 ± 46.1	48.8 ± 2.0	0.149

Notes: All variables are stated as Mean ± SD (ANOVA) unless stated otherwise. ^aCategorical variables using the Chi-square test are stated as absolute numbers. *p<0.05.

Abbreviations: %LAA₋₉₅₀, percentage of lung attenuation area <−950 HU; %WA, percentage of wall area; BMI, Body Mass Index; COPD, chronic obstructive pulmonary disease; FEV₁/FVC, forced expiratory volume in one second to forced vital capacity ratio; FEV₁pp, forced expiratory volume in one-second percentage predicted; GOLD, Global Initiative of Chronic Obstructive Lung Disease; MoCA-Ina, Montreal cognitive assessment – Indonesian version; PA:A ratio, pulmonary artery to aorta ratio; PMA, pectoralis muscle area; PMD, pectoralis muscle density; HIF-1α, Hypoxia-inducible factor one alpha; QCT, quantitative CT.

Table 2 Correlation of QCT Parameters, Lung Function, HIF-1α, and Clinical Factors with MoCA-Ina Score

Parameter	MoCA-Ina Score
	r	p
Quantitative CT
%LAA−950, %	0.15	0.103
%WA, %	0.14	0.139
PA:A ratio	−0.10	0.276
PMA, mm^2	0.08	0.386
PMD, HU	0.09	0.325
Clinical
Age, years	−0.09	0.32
Education duration, years	0.40	< 0.001*
COPD duration, years	0.04	0.70
BMI, kg/m^2	0.15	0.124
Brinkman index, cigarette-years	0.11	0.259
FEV1/FVC, %	0.02	0.822
FEV1 pp, %	0.14	0.150
HIF-1α, pg/mL	−0.15	0.105

Notes: All results were obtained from the Pearson test. *p<0.05.

Abbreviations: %LAA₋₉₅₀, percentage of lung attenuation area <−950 HU; %WA, percentage of wall area; BMI, Body Mass Index; COPD, chronic obstructive pulmonary disease; FEV₁/FVC, forced expiratory volume in one second to forced vital capacity ratio; FEV₁pp, forced expiratory volume in one-second percentage predicted; HIF-1α, Hypoxia-inducible factor 1α; MoCA-Ina, Montreal cognitive assessment – Indonesian version; PA:A ratio, pulmonary artery to aorta ratio; PMA, pectoralis muscle area; PMD, pectoralis muscle density; QCT, quantitative CT.

Table 3 Comparison of QCT Parameters, Lung Function, HIF-1α, and Clinical Factors with MoCA-Ina Score

Parameter	MoCA-Ina Total Score		p
	< 26 (n = 84)	≥ 26 (n = 30)
PA:A ratio^a
< 1	71 (62.3%)	25 (21.9%)	1.00
≥ 1	13 (11.4%)	5 (4.4%)
GOLD^b
GOLD I	10 (8.8%)	6 (5.3%)	0.47
GOLD II	27 (23.7%)	12 (10.5%)
GOLD III	34 (29.8%)	9 (7.9%)
GOLD IV	13 (11.4%)	3 (2.6%)
COPD Group^b
Group A	25 (21.9%)	6 (5.3%)	0.14
Group B	18 (15.8%)	12 (10.5%)
Group E	41 (36%)	12 (10.5%)
HIF-1α
> 49.8 pg/mL	38 (33.3%)	19 (16.7%)	0.09
≤ 49.8 pg/mL	46 (40.4%)	11 (19.6%)
Age
≥ 60 years	59 (51.8%)	18 (15.8%)	0.30
< 60 years	25 (21.9%)	12 (10.5%)
BMI
≥ 18.5	55 (48.2%)	28 (24.6%)	0.003*
< 18.5	29 (25.4%)	2 (1.8%)
Gender^a
Men	76 (66.7%)	25 (21.9%)	0.32
Women	8 (7%)	5 (4.4%)
Education duration
≥ 12 years	47 (41.2%)	25 (21.9%)	0.008*
< 12 years	37 (32.5%)	5 (4.4%)
Smoking status^a
Yes	73 (64%)	23 (20.2%)	0.24
No	11 (9.6%)	7 (6.1%)
Brinkman index^b
Mild	22 (19.3%)	11 (9.6%)	0.18
Moderate	28 (24.6%)	5 (4.4%)
Severe	34 (29.8%)	14 (12.3%)
Hypertension
Yes	41 (36%)	12 (10.5%)	0.41
No	43 (37.7%)	18 (15.8%)

Notes: All results were obtained from the chi-square test unless stated otherwise. ^aFisher-Exact. ^bLikelihood Ratio. *p < 0.05.

Abbreviations: BMI, Body Mass Index; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative of Chronic Obstructive Lung Disease; MoCA-Ina, Montreal cognitive assessment – Indonesian version; PA:A ratio, pulmonary artery to aorta ratio; HIF-1α, Hypoxia-inducible factor one alpha.

Table 4 Predictor Value Toward CI

Parameter	Unstandardized β	Standardized Coefficient β	t	p	Collinearity
					Tolerance	VIF
%LAA−950	0.11	0.25	2.36	0.02*	0.65	1.53
%WA	0.04	0.09	1.01	0.31	0.86	1.15
HIF-1α	−0.004	−0.12	−1.36	0.18	0.94	1.07
FEV1 pp	0.03	0.17	1.70	0.09	0.76	1.32
Education duration	0.32	0.30	3.23	0.01*	0.82	0.12
BMI	0.08	0.01	0.91	0.36	0.64	0.16

Notes: R² = 0.23; adjusted R² = 0.19, p < 0.001 *p < 0.05

Abbreviations:%LAA₋₉₅₀, percentage of lung attenuation area <−950 HU; %WA: percentage of wall area; BMI, body mass index; CI, cognitive impairment; FEV₁pp, forced expiratory volume in one-second percentage predicted; HIF-1α, Hypoxia inducible factor one alpha.

Table 5 Qualification Measurement of Path Analysis with Cognitive Impairment

Assessment	Value
n =114; X^2(df) = 4.73(4); p = 0.32
Comparative Fit Index (CFI)	0.99
Bollen’s Incremental Fit Index (IFI)	0.99
Tucker -Lewis Index (TLI)	0.94
Bentler-Bonett Non-normed Fit Index (NNFI)	0.94
Bentler-Bonett Normed Fit Index (NFI)	0.94
Goodness of Fit Index (GFI)	1.00
Root mean square error of approximation (RMSEA)	0.04
Standardized root mean square residual (SRMR)	0.03

Table 6 The Regression Coefficient of Path Analysis with Cognitive Impairment

Predictor	Output	Estimation	Std. Error	p	95% CI (lower;upper)	Standardized
%LAA−950	MoCA-Ina	0.09	0.04	0.03*	0.01;0.17	0.21
%WA	MoCA-Ina	0.06	0.04	0.11	−0.01;0.14	0.13
Age	MoCA-Ina	−0.06	004	0.12	−0.14;0,02	−0.13
Education duration	MoCA-Ina	0.35	0.09	<0.001*	0.18;0.52	0.34
HIF-1α	MoCA-Ina	−0.004	0.003	0.21	−0.009;0.002	−0.10
FEV1 pp	MoCA-Ina	0.04	0.02	0.02*	0.006; 0.07	0.22
%LAA−950	HIF-1α	0.09	1.34	0.94	−2.53;2.71	0.007
%WA	HIF-1α	0.05	1.34	0.97	−2.58;2.68	0.004
Age	HIF-1α	0.73	1.35	0.59	−1.93;3.38	0.05
Education duration	HIF-1α	−4.98	2.88	0.08	−10.62;0.65	−0.16
FEV1 pp	HIF-1α	0.63	0.55	0.26	−0.46;1.71	0.12
%LAA−950	FEV1 pp	−1.03	0.20	<0.001*	−1.43;-0.64	−0.43
Education duration	FEV1 pp	0.96	0.48	0.04*	0.03;1.89	0.16
%WA	FEV1 pp	−0.12	0.27	0.60	−0.56;0.33	−0.04
Age	FEV1 pp	0.40	0.23	0.07	−0.04;0.84	0.15

Notes: R² FEV₁ pp= 0.25. R² HIF-1α = 0.04. R² CI= 0.22. *p < 0.05. %LAA-950: percentage of lung attenuation area <−950 HU; %WA: percentage of wall area; FEV1pp: forced expiratory volume in one-second percentage predicted; HIF-1α: Hypoxia-inducible factor 1α; MoCA-Ina: Montreal cognitive assessment – Indonesian version;

Figure 2 Path analysis model with cognitive impairment. Both %LAA₋₉₅₀ and education duration directly and indirectly through FEV₁ pp contribute to CI development.

Abbreviations: %LAA₋₉₅₀, percentage of lung attenuation area <−950 HU; CI, cognitive impairment; FEV₁ pp, forced expiratory volume in one-second percentage predicted.

Figure 3 Proposed Mechanism of CI Development in COPD. ① Duration of education affects directly in CI, ② Duration of education affects indirectly in CI through FEV₁ pp, ③ FEV₁ pp affects directly in CI, ④ %LAA indirectly affects in CI through FEV₁ pp, ⑤ %LAA directly affects in CI, ⑥ Chronic cellular hypoxia and low-grade inflammation induce HIF-1α expression that cause neuron cell apoptosis and CI, ⑦ BMI correlates with CI, ⑧ Duration of COPD correlates with CI, ⑨ Duration of COPD that correlates with %WA, PA:A, and PM, ⑩ Age correlates with HIF-1α, ⑪ Duration of COPD correlates with CI, ⑫ Age correlates with FEV₁, ⑬ Duration of COPD correlates with FEV₁, ⑭ BMI correlates with FEV₁.

Siraj RA. Comorbid Cognitive Impairment in Chronic Obstructive Pulmonary Disease (COPD): current Understanding, Risk Factors, Implications for Clinical Practice, and Suggested Interventions. Medicina. 2023;59(4). doi:10.3390/medicina59040732

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