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Assessment of incidence of cerebral vascular diseases and prediction of stroke

risk in chronic obstructive pulmonary disease patients using multimodal
biomarkers

Article  in  The Clinical Respiratory Journal · January 2023

DOI: 10.1111/crj.13587

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DOI: 10.1111/crj.13587

ORIGINAL ARTICLE

Assessment of incidence of cerebral vascular diseases and

prediction of stroke risk in chronic obstructive pulmonary
disease patients using multimodal biomarkers

Marwa Y. Badr 1 | Amira A. Elkholy 2 | Sara M. Shoeib 3 |

Marwa G. Bahey 4 | Esraa A. Mohamed 4 | Alaa M. Reda 5

1
Neurology unit, Neuropsychiatry
Department, Faculty of Medicine, Tanta
University, Egypt
2
Pulmonology Department, Faculty of
Medicine, Tanta University, Egypt
3
Clinical Pathology Department, Faculty
of Medicine, Tanta University, Egypt
4
Medical Microbiology and immunology
Department, Faculty of Medicine, Tanta
University, Egypt
5
Diagnostic Radiology Department,
Faculty of Medicine, Tanta University,
Egypt
Correspondence
Marwa Y. Badr, Neurology unit,
Neuropsychiatry Department, Faculty of
Medicine, Tanta University, Egypt.
Email: drmoroneuro@yahoo.com
Funding information
This research did not receive any
donations from funding agencies in the
public, commercial, or not-for-profit
sectors.
Abstract
Background: Early assessment of cerebrovascular disease in chronic obstruc-
tive pulmonary disease (COPD) patients is an important issue for a favorable
influence on the quality of life.
Methodology: This cross-sectional case–control study was conducted on
38 eligible COPD patients (mean age 55.5 ± 11.5, 25 males, and 13 females)
and 26 age-/sex-matched healthy controls. All participants were subjected to
stroke risk screening instruments that included the Stroke Riskometer™, the
Framingham 10-Year Risk Score, the stroke risk screening tool (the Depart-
ment of Disease Control of Thailand), the My Risk Stroke Calculator, and Q
Stroke. Radiologically, diffusion tensor imaging (DTI) and echo-gradient MRI
(T2 star) T2 star imaging were done. Color-coded duplex sonography was
done. Laboratory investigations included C-reactive protein (CRP), serum
amyloid A, plasma fibrinogen level, serum IL6, 8-Isoprostane, vWF and uri-
nary albumin creatinine ratio.
Results: Stroke risk screening instruments revealed a significant increase in
COPD patients. DTI showed a significant bilateral reduction in fractional isot-
ropy and a significant bilateral increase in mean diffusivity of white matter
through many areas in COPD patients. Patients also had a significant increase
of intima–media thickness, presence of atherosclerotic focal thicknesses or pla-
ques on duplex sonography. There was a significant elevation of CRP, serum
amyloid A, plasma fibrinogen level, serum IL6, 8-isoprostane, von Willebrand
factor (vWF), and urinary albumin creatinine ratio in COPD patients.
Conclusion: COPD patients had an increased risk for stroke that could be
assessed on stroke risk screening instruments, DTI, T2 star, duplex sonogra-
phy, and laboratory investigation and could be correlated with the severity of
the disease.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.

Clin Respir J. 2023;1–18. wileyonlinelibrary.com/journal/crj 1

2 BADR ET AL.
KEYWORDS
biomarkers, brain imaging, cerebrovascular disease, COPD, duplex, laboratory
investigations, stroke risk
1 | INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is now
considered one of the three main leading causes of death
worldwide, about 3 million people died of COPD in 2012.
Indoor and outdoor pollutants can cause COPD in people
who do not smoke. Despite COPD being a preventable
and treatable disease, it represents a major health
problem due to its complications and systemic
manifestations.1
Previous studies have reported that patients with
COPD no exacerbations (COPDne) or COPDe are at
increased risk of stroke. However, the risk of stroke for
patients with COPDe is not completely understood. COPD
is associated with chronic inflammation, oxidative stress,
and increased inflammatory cells not only in airways and
lung parenchyma but also in systemic circulation, which
may play a role in associated comorbid conditions.2,3
Risk stratification of stroke is clinically useful because
it can help inform patients of the risk of stroke, allowing
them to improve their lifestyle or make an informed medi-
cal decision. Therefore, a series of biomarkers reflecting
inflammation, hemostasis, thrombosis, endothelial func-
tion, or neurohormonal activity have been evaluated as
potential tools in an effort to improve risk prediction of
future stroke and thereby avert future events.4–6
There has been an increasing emphasis on the
identification of markers that represent even earlier
stages of vascular brain disease. In this respect, white
matter microstructure, as assessed with diffusion tensor
imaging (DTI), has received increasing interest.7,8
Intracranial atherosclerosis is a significant risk factor
for ischemic strokes and transient ischemic attacks
(TIAs), accounting for about 10% of such events and can
be assessed by transcranial Doppler (TCD) ultrasonogra-
phy. The physiologic data obtained from TCD are com-
plementary to structural data obtained from various
modes of currently available vascular imaging.9,10
2 | AIM O F TH E WOR K
This research was conducted to assess incidence of cere-
bral vascular diseases and predict risk for stroke in
patients with COPD, using potential biomarkers includ-
ing laboratory, imaging (DTI), and TCD for possible,
early recognition and prevention.
3 | S U B J E C T S A N D ME T H O D S
3.1 | Subjects
This cross-sectional case–control study was conducted on
38 COPD patients attending inpatients and outpatients’
clinics of the chest and neuropsychiatry departments,
Tanta university hospitals in the period from December
1, 2021 to the end of May 2022. A total of 26 healthy
control subjects who matched the patient’s age, sex, and
educational level were also included for analysis and
comparison.
The study protocol was approved by the local institu-
tional ethics committee of the faculty of medicine
(Approval No: 35031/11/21), Tanta University, and
informed consent was obtained from each participant
before enrollment.
3.1.1 | Inclusion criteria
This included the following: (1) participants (patients and
controls) aged above 40 years old and (2) COPD patients
diagnosed depending upon grading of chronic obstructive
pulmonary disease refined (ABCD) assessment tool and
Global Initiative for Chronic Obstructive Lung Disease
(GOLD) criteria.11
3.1.2 | Exclusion criteria
(1) Participants with other concomitant lung diseases.
(2) Patients with previous stroke, dementia, other neuro-
logic diseases, major head trauma, or severe organic ill-
ness. (3) Participants with atrial fibrillation,
cardiomyopathy, and heart failure. (4) Patients with vas-
culitides. (5) Failure to comply with research protocol.
(6) The presence of any contraindication for undergoing
MRI scanning (e.g., claustrophobia and pacemaker).
3.2 | Methods
Patients were subjected to history taking including age,
smoking index, medical comorbidities, and complete
clinical examination (general, local chest, and neurologi-
cal examinations).
BADR ET AL.
3.2.1 | Assessment of COPD status
All participants were evaluated using refined ABCD
assessment tool (based on severity of symptoms assess-
ment using modified Medical Research Council Dyspnea
Scale, mMRC; COPD Assessment Test, CAT™ score,
Arabic version; and assessment of risk of exacerbations)
and the GOLD criteria (based on spirometrically con-
firmed diagnosis via post-bronchodilator, post-BD, and
forced expiratory volume in 1 second, FEV1/FVC < 0.7),
and then assessment of airflow limitation grade based on
FEV1% was predicted.11 These assessments were carried
out by a qualified pulmonology consultant.
3.2.2 | Risk stratification of stroke
All patients and control subjects were subjected to risk
stratification of stroke using five existing stroke risk
screening tools including (1) the Stroke Riskometer™,
(2) the Framingham 10-Year Risk Score, (3) the stroke
risk screening tool (the Department of Disease Control of
Thailand), (4) the My Risk Stroke Calculator, and (5) Q
Stroke, which were included and identified.12–15 These
tools were carried out by a qualified neuropsychiatric
consultant.
3.2.3 | Radiological evaluation
All subjects were submitted to brain imaging that
included white matter changes and diffusion MRI using
DTI and echo-gradient MRI (T2 star).7,8
MR imaging was done at 1.5 T (GE Signa Explorer)
by a standard eight-channel head coil. The slice thickness
was 4 mm, the matrix was 256  256, and the field of
view was 220–240 mm. Axial 3D DTI was achieved using
a single-shot spin-echo echo-planar imaging
(TR/TE = 7400/60 ms, 56 slices, acquisition matrix of
112  112 with pixel size of 2  2  2 mm3, interpolated
to 1  1  2 mm3, 60 diffusion gradient directions with
b = 1000 s/mm2, and three repeats of b = 0).16 Post-
processing was performed using MRI workstation soft-
ware (ADW 4.7 Vantage, GE Medical Systems) by GE
Software devised for tractography. The analysis was
based on the evaluation of DTI parameters; fractional
anisotropy (FA), mean diffusivity (MD), and relative
apparent diffusion coefficient values were assessed by
placing small regions of interest (ROIs) measuring
2  2 mm3 in different white matter areas in both cere-
bral hemispheres. All values were normalized to the
values from the white matter of controlled volunteers to
obtain relative values of all parameters.16,17
3
T2*-based imaging includes making gradient echo
(GRE) sequences more sensitive to T2* decay by chang-
ing user-selectable parameters such as echo time (TE),
flip angle, and repetition time (TR) in an appropriate
way. With these T2*-weighted sequences, the lesion,
structures, or areas of dephasing are shown as dark areas,
leading to their detection or characterization.18
3.2.4 | Color-coded duplex ultrasonography
evaluation
All subjects were subjected to evaluation of extra- and
intracranial carotid and vertebral vessels using color-
coded duplex ultrasonography. It is a noninvasive
maneuver that depends on using a pulsed Doppler system
with low transmitter frequency. This method allows
blood flow velocities to be recorded from basal cerebral
arteries through the intact skull by using transtemporal,
suboccipital, and transorbital windows. The Doppler sig-
nal obtained is assigned to a specific artery based on indi-
rect parameters: the depth of the sample volume, the
position of the transducer, and the flow direction.9,10
The extracranial carotid system was assessed by a lin-
ear array transducer of multifrequency (3–12) MHZ, real
time, sagittal, coronal, and axial views, with measure-
ment of intima–media thickness (IMT) average, peak sys-
tolic velocity (PSV), end diastolic velocity (EDV), and
detection of the presence of focal thickness or plaque in
either common carotid artery (CCA), internal carotid
artery (ICA), or external carotid artery (ECA). Intracra-
nial vessels were assessed by a phased array transducer of
multifrequency (1–3) MHZ, transaxial, mesencephalic
view through a temporal window using a Philips Ultra-
sound, Bothel, WA 98021 USA device.9,10
3.2.5 | Laboratory investigations
Subjects were also submitted to laboratory investigations
that included the following:
1. Routine laboratory test results were obtained from the
laboratory reports and serum levels of C-reactive pro-
tein (CRP), serum amyloid A, plasma fibrinogen level,
and urinary albumin creatinine ratio (UACR).5,19
2. Specific laboratory investigations:
• Blood samples: 5 ml of venous blood was drawn under
complete aseptic conditions into plain tube and
sodium citrated tube and then centrifuged at 3000 g
for 15 min. Separated serum and plasma samples were
aliquoted and stored at 20 C until used.
4 BADR ET AL.
• The serum was used for:
1. Measurement of serum level of 8-isoprostane using
8-isoprostane ELISA kit from Eagle Biosciences (cata-
log number: 8IS39-K01).20
2. Measurement of serum IL-6 using enzyme-linked
immunosorbent assay kit for human IL-6 from
Elabscience (catalog no: E-EL-H6156).19
• The plasma was used for:
1. Measurement of plasma levels of vWF:Ag using
human von Willebrand factor antigen (vWF:Ag)
ELISA kit from MyBioSource (catalog number:
MBS733078).5
3.3 | Statistical analysis
Statistical analysis was carried out using the SPSS soft-
ware statistical computer package V17. The range and
mean ± standard deviation (SD) were measured for
quantitative data. For qualitative data, comparison
between two or more groups was conducted by chi-
square test (X2). Correlation analysis was performed by
Pearson’s correlation and Spearman’s rho correlation
tests. Significance was adopted at p < 0.05 for interpreta-
tion of results.21
4 | R E SUL T S
This study included 38 COPD patients (mean age 55.5
± 11.5 years, 25 males (65.79%), 13 females (34.21%))
and 26 controls (mean age 55 ± 10 years, 17 males
(65.38%), and 9 females(34.62%)). Patients had a mean
smoking index of 47.5 ± 32.5 pack/year, 20 (52.63%) of
them were smokers, 8 (21.05%) of them were ex-
smokers, and the remaining 10 (26.32%) were non-
smokers (%). Controls had a mean smoking index of
27.5 ± 12.5 pack/year, 7 (26.92%) of them were smokers,
3 (11.54%) of them were ex-smokers, and the remaining
16 (61.54%) were nonsmokers. Among patient groups,
19 (50%) had comorbidities hypertension (18), diabetes
mellitus (7), chronic kidney disease (3), dyslipidemia (2),
and ischaemic heart disease (1). Besides, these comor-
bidities showed nonsignificant positive correlation with
Stroke Riskometer™ (5-year stroke risk %), Stroke
Riskometer™ (10-year stroke risk %), Framingham
10-Year Risk Score (%), My Risk Stroke Calculator, and
QRISK®3 10-year risk calculator (%) (p value 0.233,
0.270, 0.157, 0.603, and 0.157, respectively, for previous
variables).
4.1 | Assessment of COPD status results
Assessment of COPD severity in patients using refined
ABCD assessment tool and the GOLD criteria showed a
significant reduction of post-BD FEV1/FVC ratio and
FEV1 (% predicted) level in COPD patients than in con-
trols with p value <0.001 for each. There was a significant
increase of mMRC, CAT score, and risk of exacerbations
in COPD patients than in controls with p value <0.001
for each. According to ABCD assessment tool grades,
2 (5.26%) COPD patients were classified as Group A,
9 (23.68%) COPD patients were classified as Group B,
14 (36.84%) COPD patients were classified as Group C,
and 13 (34.21%) COPD patients were classified as
Group D. According to the GOLD criteria, 1 (2.63%)
COPD patient was classified as Group 1, 7 (18.42%)
COPD patients were classified as Group 2, 22 (57.89%)
COPD patients were classified as Group 3, and 8 (21.05%)
COPD patients were classified as Group 4.
4.2 | Risk stratification of stroke results
The study showed a significant increase of each Stroke
Riskometer™ (5-year stroke risk), Stroke Riskometer™
(10-year stroke risk), Framingham 10-Year Risk Score,
My Risk Stroke Calculator, and QRISK®3 10-year risk
calculator in COPD patients than in controls with p value
<0.001 for each. According to the stroke risk screening
tool, 4 (10.53%) patients were classified as having low
risk, 14 (36.84%) patients were classified as having cau-
tious risk, and 20 (52.63%) patients were classified as hav-
ing high risk, with statistically highly significant
differences (p < 0.001) than their matched controls.
Stroke Riskometer™ (5-year stroke risk), Stroke
Riskometer™ (10-year stroke risk), Framingham 10-Year
Risk Score, My Risk Stroke Calculator, and QRISK®3
10-year risk calculator were all directly correlated with
mMRC, CAT score, risk of exacerbations, ABCD assess-
ment tool grades, and the GOLD criteria but inversely
correlated with spirometric data, post-BD FEV1/FVC
ratio and FEV1 (% predicted) level (see Supporting
Information and Tables 4 and 5).
4.3 | Radiological results
DTI showed a significant reduction in fractional isotropy
with a significant increase in MD in many areas includ-
ing the superior occipitofrontal fasciculus (SOFF), infe-
rior occipitofrontal fasciculus (IOFF), arcuate fibers,
corpus callosum, frontal subcortical tract, parietal subcor-
tical tract, temporal subcortical tract, cingulum, corona
BADR ET AL. 5

radiata, internal capsule, cerebral peduncle, and corti-
cospinal tract in both hemispheres in COPD patients
than in controls (see Supporting Information, Table 1,
and Figure 1).
T2 star revealed either normal findings in 18 (47.37%)
COPD patients versus in 21 (80.77%) controls or micro-
bleeds in 20 (52.63%) COPD patients versus in 5 (19.23%)
controls with statistically significant differences for both
previous variables with p value 0.007 (see Supporting
Information, Table 1, and Figure 2).
MD of the SOFF, IOFF, arcuate fibers, corpus callo-
sum, frontal subcortical tract, parietal subcortical tract,
temporal subcortical tract, cingulum, corona radiata, inter-
nal capsule, cerebral peduncle, and corticospinal tract in
both hemispheres was all directly correlated with mMRC,
CAT score, risk of exacerbations, ABCD assessment tool

TABLE 1 DTI and T2 star in COPD patients and control subjects

Groups T-test

DTI Patient Control t p value

SOFF (FA) RT Range 0.19–0.44 0.31–0.44 4.152 <0.001*
Mean ± SD 0.299 ± 0.076 0.366 ± 0.034
LT Range 0.2–0.45 0.34–0.45 4.121 <0.001*
Mean ± SD 0.304 ± 0.080 0.372 ± 0.033
SOFF (MD) RT Range 4.6–7.4 4.66–5.2 4.332 <0.001*
Mean ± SD 5.720 ± 1.025 4.842 ± 0.137
LT Range 6.63–9 6.63–7 4.339 <0.001*
Mean ± SD 7.521 ± 0.779 6.851 ± 0.118
IOFF (FA) RT Range 0.16–0.38 0.3–0.38 6.475 <0.001*
Mean ± SD 0.268 ± 0.064 0.353 ± 0.022
LT Range 0.17–0.39 0.32–0.38 5.823 <0.001*
Mean ± SD 0.276 ± 0.063 0.349 ± 0.017
IOFF (MD) RT Range 7.44–10 7.44–7.91 4.177 <0.001*
Mean ± SD 8.342 ± 0.798 7.681 ± 0.127
LT Range 4.46–7.3 4.55–4.99 4.202 <0.001*
Mean ± SD 5.652 ± 1.009 4.812 ± 0.153
Arcuate F (FA) RT Range 0.2–0.43 0.33–0.41 2.255 0.028*
Mean ± SD 0.358 ± 0.054 0.383 ± 0.018
LT Range 0.21–0.44 0.36–0.42 2.601 0.012*
Mean ± SD 0.363 ± 0.051 0.390 ± 0.015
Arcuate F (MD) RT Range 4.68–7.4 4.77–4.97 1.174 0.245
Mean ± SD 4.994 ± 0.538 4.869 ± 0.063
LT Range 4.18–6.8 4.19–4.3 3.100 0.003*
Mean ± SD 4.603 ± 0.583 4.247 ± 0.029
CC (FA) Range 0.4–0.64 0.56–0.63 4.000 <0.001*
Mean ± SD 0.524 ± 0.072 0.582 ± 0.018
CC (MD) Range 3.37–6 3.38–3.48 3.109 0.003*
Mean ± SD 3.866 ± 0.679 3.451 ± 0.027
Frontal subcortical tract (FA) RT Range 0.07–0.3 0.2–0.29 7.300 <0.001*
Mean ± SD 0.156 ± 0.060 0.248 ± 0.028
LT Range 0.05–0.25 0.15–0.24 4.810 <0.001*
Mean ± SD 0.122 ± 0.055 0.180 ± 0.032
(Continues)
6 BADR ET AL.

TABLE 1 (Continued)

Groups T-test

DTI Patient Control t p value

Frontal subcortical tract (MD) RT Range 5.11–8 5.11–5.25 7.520 <0.001*
Mean ± SD 6.461 ± 0.861 5.187 ± 0.040
LT Range 4.53–7 4.55–4.7 8.079 <0.001*
Mean ± SD 5.798 ± 0.729 4.638 ± 0.049
Parietal subcortical tract (FA) RT Range 0.06–0.28 0.2–0.28 5.987 <0.001*
Mean ± SD 0.149 ± 0.060 0.223 ± 0.025
LT Range 0.03–0.23 0.15–0.21 5.219 <0.001*
Mean ± SD 0.131 ± 0.057 0.190 ± 0.015
Parietal subcortical tract (MD) RT Range 5.01–7.5 5.03–5.15 7.711 <0.001*
Mean ± SD 6.373 ± 0.831 5.112 ± 0.032
LT Range 4.87–7.56 4.87–5 8.704 <0.001*
Mean ± SD 6.387 ± 0.854 4.925 ± 0.044
Temporal subcortical tract (FA) RT Range 0.05–0.29 0.19–0.28 7.003 <0.001*
Mean ± SD 0.149 ± 0.059 0.235 ± 0.026
LT Range 0.01–0.19 0.12–0.17 3.561 0.001*
Mean ± SD 0.104 ± 0.044 0.136 ± 0.017
Temporal subcortical tract (MD) RT Range 3.84–6.5 3.85–3.99 11.018 <0.001*
Mean ± SD 5.135 ± 0.563 3.912 ± 0.045
LT Range 7.69–10 7.7–7.81 6.299 <0.001*
Mean ± SD 8.592 ± 0.674 7.757 ± 0.036
Cingulum (FA) RT Range 0.24–0.48 0.37–0.47 7.521 <0.001*
Mean ± SD 0.301 ± 0.066 0.405 ± 0.030
Lt Range 0.36–0.66 0.56–0.65 8.583 <0.001*
Mean ± SD 0.438 ± 0.087 0.590 ± 0.025
Cingulum (MD) RT Range 2.93–5.5 2.93–3.04 9.147 <0.001*
Mean ± SD 4.065 ± 0.591 3.001 ± 0.034
LT Range 3.5–6 3.51–3.66 6.011 <0.001*
Mean ± SD 4.533 ± 0.808 3.577 ± 0.040
Corona radiata (FA) RT Range 0.14–0.4 0.31–0.39 7.053 <0.001*
Mean ± SD 0.274 ± 0.055 0.355 ± 0.024
LT Range 0.28–0.53 0.42–0.51 6.935 <0.001*
Mean ± SD 0.382 ± 0.058 0.467 ± 0.026
Corona radiata (MD) RT Range 5.01–7.3 5.04–5.16 9.798 <0.001*
Mean ± SD 6.039 ± 0.485 5.103 ± 0.032
LT Range 5.61–8 5.62–5.77 6.232 <0.001*
Mean ± SD 6.507 ± 0.643 5.718 ± 0.045
Internal capsule (FA) RT Range 0.25–0.5 0.4–0.49 6.406 <0.001*
Mean ± SD 0.349 ± 0.070 0.442 ± 0.027
LT Range 0.25–0.52 0.42–0.51 6.768 <0.001*
Mean ± SD 0.354 ± 0.079 0.463 ± 0.027
(Continues)
BADR ET AL. 7

TABLE 1 (Continued)

Groups T-test

DTI Patient Control t p value

Internal capsule (MD) RT Range 4.92–7.41 4.91–5.1 9.267 <0.001*
Mean ± SD 6.079 ± 0.599 4.985 ± 0.054
LT Range 4.35–7 4.37–4.55 4.068 <0.001*
Mean ± SD 5.105 ± 0.788 4.474 ± 0.046
Cerebral peduncle (FA) RT Range 0.49–0.75 0.65–0.74 6.590 <0.001*
Mean ± SD 0.600 ± 0.064 0.687 ± 0.026
LT Range 0.34–47 0.51–0.6 0.775 0.441
Mean ± SD 1.696 ± 7.548 0.545 ± 0.030
Cerebral peduncle (MD) RT Range 4.44–7 4.45–4.6 6.627 <0.001*
Mean ± SD 5.457 ± 0.711 4.529 ± 0.049
LT Range 7.05–9.4 7.06–7.22 4.614 <0.001*
Mean ± SD 7.718 ± 0.630 7.146 ± 0.044
Corticospinal tract (FA) RT Range 0.24–0.51 0.41–0.51 7.958 <0.001*
Mean ± SD 0.342 ± 0.068 0.455 ± 0.031
LT Range 0.28–0.55 0.39–0.55 6.817 <0.001*
Mean ± SD 0.363 ± 0.083 0.480 ± 0.034
Corticospinal tract (MD) RT Range 4.03–7.6 4.05–4.22 7.262 <0.001*
Mean ±SD 5.187 ± 0.731 4.143 ± 0.049
LT Range 5.71–8 5.71–5.89 7.789 <0.001*
Mean ± SD 6.818 ± 0.660 5.805 ± 0.049
Chi-square N % N % X2 p value
T2 star Normal 18 47.37 21 80.77 7.235 0.007*
Microbleeds 20 52.63 5 19.23

Abbreviations: CC, corpus callosum; COPD, chronic obstructive pulmonary disease; DTI, diffusion tensor imaging; FA, fractional anisotropy; IOFF, inferior
occipitofrontal fasciculus; LT, left; MD, mean diffusivity; RT, right; SOFF, superior occipitofrontal fasciculus.
*Statistically significant p < 0.05.

grades, and the GOLD criteria but inversely correlated
with FEV1/FVC ratio and FEV1 level.
FA of the SOFF, IOFF, arcuate fibers, corpus callo-
sum, frontal subcortical tract, parietal subcortical tract,
temporal subcortical tract, cingulum, corona radiata,
internal capsule, cerebral peduncle, and corticospinal
tract in both hemispheres was all directly correlated with
FEV1/FVC ratio and FEV1 level but inversely correlated
with mMRC, CAT score, risk of exacerbations, ABCD
assessment tool grades, and the GOLD criteria.
4.4 | Color-coded duplex
ultrasonography results
Color-coded duplex ultrasonography showed a significant
increase of IMT in COPD patients than in controls
(p value <0.001). Focal thicknesses were present in
15 (39.47%) COPD patients with statistically significant
differences than their matched controls with p value
0.038, whereas plaques were present in nine (23.68%)
COPD patients with statistically significant differences
than their matched controls with p value 0.032. Mean-
while, there were no statistically significant differences
regarding location, echogenicity, thickness, and luminal
diameter stenosis of either focal thickness or plaque in
COPD patients than in controls (Table 2) (Figure 3). IMT,
thicknesses of both focal thicknesses and plaques, and
luminal diameter stenosis of both focal thicknesses and
plaques were positively correlated with mMRC, CAT
score, risk of exacerbations, ABCD assessment tool
grades, and the GOLD criteria but negatively correlated
with FEV1/FVC ratio and FEV1 level (see Supporting
Information and Tables 4 and 5).
8 BADR ET AL.
4.5 | Laboratory results
Laboratory investigations revealed a significant eleva-
tion of serum inflammatory markers including CRP,
fibrinogen, amyloid A, and IL6 in COPD patients than
in controls (p value <0.001). There was also a signifi-
cant increase of serum oxidative stress marker
8-isoprostane in COPD patients than in controls
(p value <0.001). Besides, there was a significant
F I G U R E 1 Diffusion tensor imaging (DTI)
study in chronic obstructive pulmonary disease
(COPD) patients with upper panel showing
reduced FA in the following from RT to LT side:
RT frontal subcortical tract and LT internal
capsule; middle panel showing reduced
apparent diffusion coefficient (ADC) in the
following from RT to LT side: LT temporal lobe
and RT parietal lobe; and lower panel showing
positioning of the region of interest (ROI) used
to measure FA and mean diffusivity
(MD) including RT to LT side: RT corticospinal
tract and whole tracts
increase of serum vWF and UACR in COPD patients
than in controls (p value <0.001) (see Supporting
Information and Table 3).
Serum CRP, fibrinogen, amyloid A, IL6,
8-isoprostane, vWF, and UACR were positively correlated
with mMRC, CAT score, risk of exacerbations, ABCD
assessment tool grades, and the GOLD criteria but nega-
tively correlated with FEV1/FVC ratio and FEV1 level
(see Supporting Information and Tables 4 and 5).
BADR ET AL. 9

F I G U R E 2 MRI study in chronic

obstructive pulmonary disease (COPD) patients
with tiny low signal foci of hemosiderin of
microbleeds in the FLAIR film RT image and T2
star in LT image

TABLE 2 Duplex findings in COPD patients and control subjects

Groups T-test

Duplex findings Patient Control t p value

IMT (cm) Range 0.06–0.31 0.06–0.15 4.642 <0.001*
Mean ± SD 0.172 ± 0.070 0.105 ± 0.025
Chi-square N % N % X2 p value
Focal thickness No 23 60.53 22 84.62 4.292 0.038*
Yes 15 39.47 4 15.38
Focal thickness (location) Bifurcation CCA 1 6.67 0 0.00 5.162 0.396
Mid CCA 2 13.33 0 0.00
Distal CCA 3 20.00 3 75.00
Mid ICA 4 26.67 0 0.00
Proximal ICA 4 26.67 1 25.00
Proximal ECA 1 6.67 0 0.00
Focal thickness (echogenicity) Hyperechoic 10 66.67 3 75.00 0.101 0.750
Hypoechoic 5 33.33 1 25.00
Focal thickness (thickness, cm) Range 0.24–0.46 0.32–0.41 0.171 0.866
Mean ± SD 0.357 ± 0.074 0.350 ± 0.041
Focal thickness (luminal diameter stenosis %) Range 25–44.9 34–44.5 0.627 0.539
Mean ± SD 34.473 ± 7.119 36.875 ± 5.099
Plaque No 29 76.32 25 96.15 4.608 0.032*
Yes 9 23.68 1 3.85
Plaque (location) Bifurcation CCA 1 11.11 0 0.00 1.111 0.774
Distal CCA 4 44.44 1 100.00
Mid ICA 2 22.22 0 0.00
Proximal ICA 2 22.22 0 0.00
Plaque (echogenicity) Hyperechoic 7 77.78 1 100.00 0.278 0.598
Hypoechoic 2 22.22 0 0.00
Plaque (thickness, cm) Range 0.55–0.69 0.57–0.57 0.966 0.362
Mean ± SD 0.616 ± 0.045 0.570 ± 0.000
(Continues)
10 BADR ET AL.

TABLE 2 (Continued)

Groups T-test

Duplex findings Patient Control t p value

Plaque (luminal diameter stenosis %) Range 54–69.4 56.8–56.8 0.849 0.421
Mean ± SD 61.111 ± 4.818 56.800 ± 0.000

Abbreviations: CCA, common carotid artery; COPD, chronic obstructive pulmonary disease; ECA, external carotid artery; ICA, internal carotid artery; IMT,
intima–media thickness.
*Statistically significant p < 0.05.

F I G U R E 3 Duplex ultrasonography study in chronic obstructive pulmonary disease (COPD) patients with upper panel showing
increased intima–media thickness (IMT) (about 0.15 cm); the second panel showing homogenous hyperechoic focal thickness in the distal
common carotid artery (CCA) measuring 0.36 cm  0.20 cm, making diameter stenosis 28.3%; and the third panel showing homogenous
hyperechoic plaque in the internal carotid artery (ICA) measuring 1.00 cm  0.54 cm, making diameter stenosis 55%
BADR ET AL. 11

TABLE 3 Laboratory investigations in COPD patients and control subjects

Groups T-test

Laboratory investigations Patient Control t p value

CRP (mg/l) Range 1.9–82.3 0–10.3 3.924 <0.001*
Mean ± SD 21.582 ± 20.700 5.500 ± 2.999
Fibrinogen (g/l) Range 2.2–25.7 1.8–5.9 5.295 <0.001*
Mean ± SD 11.059 ± 6.769 3.931 ± 1.261
Amyloid A (mg/l) Range 6–77.8 2–14.9 4.085 <0.001*
Mean ± SD 26.797 ± 22.370 8.692 ± 3.352
IL6 (pg/ml) Range 6.5–25 1–8 5.804 <0.001*
Mean ± SD 11.295 ± 4.759 5.596 ± 1.843
8-isoprostane (pg/ml) Range 80–250 40–100 6.207 <0.001*
Mean ± SD 121.339 ± 38.716 70.500 ± 18.713
vWF (ng/ml) Range 8–30 5–10.5 5.755 <0.001*
Mean ± SD 14.966 ± 6.561 7.431 ± 1.388
UACR Range 20–305 9.7–35 5.023 <0.001*
Mean ± SD 112.842 ± 92.716 21.104 ± 7.081

Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; UACR, urinary albumin creatinine ratio; vWF, von Willebrand factor.
*Statistically significant p < 0.05.

T A B L E 4 Correlation of the COPD severity assessment items with risk stratification of stroke, duplex findings, and laboratory
investigations in COPD patients

Pearson correlation

Spirometry
post-BD FEV1 level Risk of
(FEV1/FVC) (% predicted) mMRC CAT score exacerbations

Variables r p value r p value r p value r p value r p value

Risk stratification Stroke 0.681 <0.001* 0.483 0.002* 0.326 0.046* 0.182 0.275 0.267 0.106
of stroke Riskometer™
(5-year stroke
risk%)
Stroke 0.685 <0.001* 0.475 0.003* 0.339 0.037* 0.203 0.221 0.279 0.090
Riskometer™
(10-year
stroke risk%)
Framingham 0.204 0.220 0.689 <0.001* 0.251 0.129 0.224 0.177 0.144 0.387
10-Year Risk
Score (%)
My Risk Stroke 0.530 0.001* 0.069 0.681 0.253 0.125 0.223 0.179 0.245 0.139
Calculator
(points)
QRISK®3 10-year 0.531 0.001* 0.605 <0.001* 0.336 0.039* 0.003 0.985 0.271 0.100
risk calculator
(%)
(Continues)
12 BADR ET AL.

TABLE 4 (Continued)

Pearson correlation

Spirometry
post-BD FEV1 level Risk of
(FEV1/FVC) (% predicted) mMRC CAT score exacerbations

Variables r p value r p value r p value r p value r p value

Duplex findings IMT (cm) 0.077 0.645 0.607 <0.001* 0.051 0.759 0.113 0.498 0.011 0.946
Focal thickness 0.120 0.671 0.360 0.188 0.005 0.987 0.028 0.921 0.014 0.962
(thickness,
cm)
Focal thickness 0.066 0.817 0.378 0.164 0.009 0.975 0.092 0.743 0.074 0.793
(luminal
diameter
stenosis %)
Plaque 0.079 0.840 0.031 0.937 0.330 0.386 0.013 0.973 0.357 0.346
(thickness,
cm)
Plaque (luminal 0.118 0.762 0.011 0.978 0.347 0.361 0.032 0.935 0.341 0.369
diameter
stenosis %)
Laboratory CRP (mg/l) 0.600 <0.001* 0.181 0.275 0.176 0.290 0.005 0.976 0.155 0.352
investigations Fibrinogen (g/l) 0.181 0.277 0.451 0.004* 0.165 0.322 0.154 0.354 0.107 0.522
Amyloid A (mg/l) 0.213 0.199 0.389 0.016* 0.265 0.108 0.378 0.019* 0.057 0.735
IL6(pg/ml) 0.417 0.009* 0.393 0.015* 0.115 0.492 0.097 0.562 0.198 0.233
8-isoprostane 0.229 0.167 0.409 0.011* 0.250 0.130 0.049 0.769 0.014 0.934
(pg/ml)
vWF (ng/ml) 0.611 <0.001* 0.284 0.084 0.055 0.741 0.023 0.891 0.209 0.208
UACR 0.452 0.004* 0.362 0.025* 0.085 0.613 0.088 0.599 0.162 0.331

Abbreviations: CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; FEV1, forced expiratory
volume in 1 second; IMT, intima–media thickness; mMRC, modified Medical Research Council; post-BD, post-bronchodilator; UACR, urinary
albumin creatinine ratio; vWF, von Willebrand factor.
*Statistically significant p < 0.05.

5 | DISCUSSION (smokers/ex-smokers or nonsmokers) or continuous

Increasing evidence associates COPD with cerebrovascu-
lar disease in the elderly. A reduced pulmonary function
is associated with an increased risk of stroke and subclin-
ical events such as silent stroke, brain atrophy, or small
vessel disease that have an impact on the quality of life.22
Patients diagnosed with COPD who were included in
this study were linked to smoking. Patients had a mean
smoking index of 47.5 ± 32.5 pack/year, 20 (52.63%) of
them were smokers, 8 (21.05%) of them were ex-smokers,
and the remaining 10 (26.32%) were nonsmokers. This
was in agreement with Wang et al. who stated that ciga-
rette smoking was the most popular and the most impor-
tant modifiable risk factor of COPD. The independent
and positive relationship was basically established
between cigarette smoking and COPD regardless that
cigarette smoking was assessed with a categorical
measure (number of cigarettes smoked).23
Regarding comorbidities recorded in this study, they
showed nonsignificant positive correlation with Stroke
Riskometer™ (5-year stroke risk %), Stroke Riskometer™
(10-year stroke risk %), Framingham 10-Year Risk Score
(%), and QRISK®3 10-year risk calculator (%). In agree-
ment with these results, Mannino et al. reported that
although stroke risk factors are common in COPD
patients, including hypertension, diabetes, and hypercho-
lesterolaemia, stroke risk in COPD might not be wholly
explained by the contribution of shared risk factors.24
O’Donnell et al. and Soderholm et al. also informed that
major risk factors for stroke such as hypertension, cur-
rent smoking, physical inactivity, diabetes mellitus, alco-
hol intake, and psychosocial stress and cardiac causes
can also be seen in COPD patients, and thus, the link
between COPD and stroke can be confounding.25,26
BADR ET AL. 13

T A B L E 5 Correlation of the ABCD assessment grades and GOLD criteria grades with risk stratification of stroke, duplex findings, and
laboratory investigations in COPD patients

Spearman’s rho correlation

ABCD assessment grades GOLD criteria grades

Variables r p value r p value

Risk stratification of stroke Stroke Riskometer™ (5-year stroke risk%) 0.181 0.275 0.417 0.009*
Stroke Riskometer™ (10-year stroke risk%) 0.138 0.407 0.389 0.016*
Framingham 10-Year Risk Score (%) 0.034 0.840 0.622 <0.001*
My Risk Stroke Calculator (points) 0.247 0.135 0.021 0.898
®
QRISK 3 10-year risk calculator (%) 0.068 0.684 0.472 0.003*
Duplex findings IMT (cm) 0.133 0.427 0.591 <0.001*
Focal thickness (thickness, cm) 0.361 0.187 0.039 0.889
Focal thickness (luminal diameter stenosis %) 0.267 0.337 0.037 0.895
Plaque (thickness, cm) 0.293 0.444 0.370 0.327
Plaque (luminal diameter stenosis %) 0.329 0.388 0.369 0.329
CRP (mg/l) 0.186 0.263 0.195 0.240
Laboratory investigations Fibrinogen (g/l) 0.113 0.501 0.440 0.006*
Amyloid A (mg/l) 0.095 0.569 0.352 0.030*
IL6 (pg/ml) 0.087 0.603 0.316 0.053*
8-isoprostane (pg/ml) 0.055 0.745 0.320 0.050*
vWF (ng/ml) 0.112 0.505 0.202 0.224
UACR 0.081 0.630 0.250 0.129

Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IMT,
intima–media thickness; UACR, urinary albumin creatinine ratio; vWF, von Willebrand factor.
*Statistically significant p < 0.05.

Assessment of COPD severity in patients using
refined ABCD assessment tool and GOLD criteria grades
showed a significant reduction of spirometry-assessed
post-brain diffusion (post-BD) FEV1/FVC ratio and FEV1
level in COPD patients than in controls. There was a sig-
nificant increase of mMRC, CAT score, and risk of exac-
erbations in COPD patients than in controls. According
to ABCD assessment tool grades, 2 (5.26%) COPD
patients were classified as Group A, 9 (23.68%) COPD
patients were classified as Group B, 14 (36.84%) COPD
patients were classified as Group C, and 13 (34.21%)
COPD patients were classified as Group D. According to
the GOLD criteria, 1 (2.63%) COPD patient was classified
as Group 1, 7 (18.42%) COPD patients were classified as
Group 2, 22 (57.89%) COPD patients were classified as
Group 3, and 8 (21.05%) COPD patients were classified as
Group 4. This was in line with Yawn who reported that
the most commonly used COPD severity classification
was the one proposed by the GOLD, which was based on
a simple spirometry grading system, patient’s symptom
burden, and their history of exacerbations.27 This also
was in agreement with Vogelmeier et al. who stated that
the spirometric definition of obstruction using a fixed
FEV1/FVC ratio of less than 0.70 has been consistent
since the first GOLD guideline. The mMRC questionnaire
and CAT were the two most widely used measures to
assess symptoms of COPD. Symptom burden and risk of
exacerbation were also further classified into GOLD
Groups A through D, which is used to guide therapy.28
The current study showed a significant increase of
each Stroke Riskometer™ (5-year stroke risk), Stroke
Riskometer™ (10-year stroke risk), Framingham 10-Year
Risk Score, My Risk Stroke Calculator, and QRISK®3
10-year risk calculator in COPD patients than in controls.
According to the stroke risk screening tool, 4 (10.53%)
patients were classified as having low risk, 14 (36.84%)
patients were classified as having cautious risk, and
20 (52.63%) patients were classified as having high risk,
with statistically highly significant differences than their
matched controls. This matched with the results obtained
by Hippisley et al., Nobel et al., Parmar et al., and Wolf
et al. who showed that early and comprehensive risk
identification would be critical to identify people at high
risk for stroke. Therefore, comprehensive stroke risk
14
screening instruments including the stroke risk screening
tool, the Framingham 10-Year Risk Score, The Stroke
Riskometer™, Q Stroke, and the My Risk Stroke Calcula-
tor were needed to assess all possible stroke risks and
potential at-risk populations that would benefit early
detection and stroke prevention planning.29–32
Stroke Riskometer™ (5-year stroke risk), Stroke
Riskometer™ (10-year stroke risk), Framingham 10-Year
Risk Score, My Risk Stroke Calculator, and QRISK®3
10-year risk calculator were all directly correlated with
mMRC, CAT score, risk of exacerbations, ABCD assess-
ment tool grades, and the GOLD criteria but inversely
correlated with FEV1/FVC ratio and FEV1 level. This
was in accordance with Gulsvik et al. who concluded that
interestingly decreased lung function expressed as
decreased FEV1 and decreased FEV1/FVC ratio in COPD
patients is correlated with an increased risk of stroke.33
In the same line, Portegies et al. reported that COPD
exacerbations were also associated with an increased risk
of stroke.34
In the present study, DTI has shown a significant
reduction in fractional isotropy with a significant
increase in MD in many areas including the SOFF, IOFF,
arcuate fibers, corpus callosum, frontal subcortical tract,
parietal subcortical tract, temporal subcortical tract, cin-
gulum, corona radiata, internal capsule, cerebral pedun-
cle, and corticospinal tract in both hemispheres in COPD
patients than in controls. These results matched with
those obtained from different studies carried by Zhang
et al., Dodd et al., Yin et al., and Helmy et al. who con-
cluded that patients with COPD had significantly reduced
white matter microstructural integrity as shown by lower
FA values and higher MD values in the white matter
pathways in many regions that included the corpus callo-
sum, cingulum, corona radiata, internal capsule, SOFF
and IOFF, frontal subcortical tract, parietal subcortical
tract, and temporal subcortical tract.35–38 Besides, Evans
et al. stated that they found that white matter diffusion
measures and microstructural integrity impairment
reflected by decreased FA and increased MD were associ-
ated with a higher risk of stroke, independent of white
matter (WM) volume, intracranial volume, white matter
lesion volume, and the presence of lacunar infarcts.39
T2 star revealed either normal findings in 18 (47.37%)
COPD patients versus in 21 (80.77%) controls or micro-
bleeds in 20 (52.63%) COPD patients versus in 5 (19.23%)
controls. This was in agreement with a large population-
based study carried by Lahousse et al. and Maclay and
MacNee, which showed that a higher prevalence of cere-
bral microbleeds was associated with COPD. It might be
that patients with COPD are at risk for microbleeds due
to comorbid processes, such as systemic inflammation
without specific cognitive consequences or other clinical
BADR ET AL.
problems.40,41 Besides, Greenberg et al. reported that
COPD would preferentially lead to the development of
deep or infratentorial microbleeds, which were thought
to occur by arteriolosclerosis on the basis of hypertensive
vasculopathy and lipohyalinosis. The risk on deep or
infratentorial microbleeds increased with severity of air-
flow limitation, dyspnea symptoms, and exacerbation
problems.42
MD of the SOFF, IOFF, arcuate fibers, corpus callo-
sum, frontal subcortical tract, parietal subcortical tract,
temporal subcortical tract, cingulum, corona radiata,
internal capsule, cerebral peduncle, and corticospinal
tract in both hemispheres was all directly correlated with
mMRC, CAT score, risk of exacerbations, and the GOLD
criteria but inversely correlated with FEV1/FVC ratio
and FEV1 level. FA of the SOFF, IOFF, arcuate fibers,
corpus callosum, frontal subcortical tract, parietal subcor-
tical tract, temporal subcortical tract, cingulum, corona
radiata, internal capsule, cerebral peduncle, and corti-
cospinal tract in both hemispheres was all directly corre-
lated with FEV1/FVC ratio and FEV1 level but inversely
correlated with mMRC, CAT score, risk of exacerbations,
ABCD assessment tool grades, and the GOLD criteria.
These results were in line with Catherine et al. who
found that lower lung function (FEV1 and FEV1/FVC)
was associated with a deterioration in white matter
macro- and microstructure evidenced by decreased FA
and increased MD.43 Besides, Yin et al. found that rela-
tive to the comparison group, severe COPD patients
showed the most extensive changes in WM integrity,
including more decreased FA and increased MD, reflect-
ing their correlation to symptom burden assessed by
mMRC and CAT score.37 Besides, Helmy et al. reported a
negative correlation between the number of exacerba-
tions and the FA values of white matter tracts, which was
not significant, whereas a significant positive correlation
between the number of exacerbations and the MD values
was seen in the majority of selected white matter tracts.38
In our study, color-coded duplex ultrasonography
showed a significant increase of IMT in COPD patients
than in controls. This was in accordance with several
studies investigating subclinical atherosclerosis accompa-
nying COPD, which have reported that high carotid IMT
(CIMT) was an important marker reflecting the early
subclinical phase of atherosclerotic disease. In a review
investigating the presence of subclinical atherosclerosis
in COPD patients, 22 studies were examined, and it was
found that CIMT was significantly higher in COPD
patients than in the control groups in all of the studies in
which CIMT was measured.44,45
Focal thicknesses were present in 15 (39.47%)
COPD patients with statistically significant differences
than their matched controls, whereas plaques were
BADR ET AL.
present in nine (23.68%) COPD patients with statisti-
cally significant differences than their matched con-
trols. Meanwhile, there were no statistically significant
differences regarding location, echogenicity, thickness,
and luminal diameter stenosis of either focal thickness
or plaque in COPD patients than in controls. Recent
studies carried by Iwamoto et al. and Lahousse et al.
have shown that carotid arterial plaque burden and
focal thickness were increased in patients with COPD
and that these plaques were more prone to rupture,
due to an increased lipid content, potentially leading
to ischemic strokes.46,47
IMT, thicknesses of both focal thicknesses and pla-
ques, and luminal diameter stenosis of both focal
thicknesses and plaques were positively correlated with
mMRC, CAT score, risk of exacerbations, ABCD
assessment tool grades, and the GOLD criteria but
negatively correlated with FEV1/FVC ratio and FEV1
level. These results matched with those of the study
carried by Kim et al., identifying a negative correlation
between FEV1 level and CIMT measurements. A previ-
ous study made by Zureik et al. also reported a signifi-
cant relationship between decreased FEV1 levels and
endothelial dysfunction and vascular wall stiffness and
the presence of atherosclerosis. Additionally, CIMT
was found to be significantly associated with GOLD-
combined assessment groups as stated by Gulbas et al.
Although previous studies reported no relationship
between COPD exacerbations and CIMT, it has also
been suggested by Golpe et al. that the increased sys-
temic inflammatory response during exacerbations may
contribute to the activation of an atherosclerotic
process.48–51 Ambrosino et al. found that the risk of
carotid plaque development was directly correlated
with GOLD-combined assessment groups in COPD
patients.52
Laboratory investigations revealed a significant ele-
vation of serum inflammatory markers including CRP,
fibrinogen, amyloid A, and IL6 in COPD patients than
in controls. There was also a significant increase of
serum oxidative stress marker 8-isoprostane in COPD
patients than in controls. Besides, there was a signifi-
cant increase of serum vWF and UACR in COPD
patients than in controls. These results matched with
those of the studies conducted by Gan et al., Barnes
et al., and Kazmierczak et al. who have shown, in
addition to lung inflammation, that a state of chronic
systemic inflammation was observed in COPD evi-
denced by increases in the serum levels of CRP, fibrin-
ogen, serum amyloid A (SAA), and pro-inflammatory
cytokine including IL-6 in COPD patients. Importantly,
these markers of systemic inflammation were elevated
even further during acute exacerbation. It was
15
conceivable that the systemic inflammation and
increased oxidative stress in COPD may independently
increase stroke risk by directly promoting cerebral vas-
cular dysfunction and thus vascular insufficiency.19,53,54
The study conducted by Gupta et al. indicated that
there was a strong relationship of UACR in patients
with COPD and the levels of microalbuminuria (MAB)
increased as the severity of COPD increased due to
hypoxia and endothelial dysfunction. As MAB was a
marker for cardiovascular and cerebrovascular risks,
patients with COPD can be routinely evaluated for the
urine test of MAB specially those who were at an
increased risk for cerebrovascular events.55 Besides,
Bartholo et al. and Polosa et al. showed that vWF
levels and relative activity have been found to be
increased in COPD, which had an impact on platelet
activation and a biomarker of endothelial dysfunction
and inflammation in COPD.56,57
Limitations of the study: It’s worth mentioning that
this study should be regarded in the perspective of a
number of shortcomings. First, the restricted number of
participants that has attributed to limited study duration,
strict selection criteria, and the high costs of neuroimag-
ing and assay kits. Second, the study could be more infor-
mative if we could do a follow-up of our patients and
evaluate the impact of proper management and preven-
tion of cerebrovascular events. Therefore, future longitu-
dinal prospective researches on a larger scale of
participants are fundamental to identify whether patients
at high risk for developing cerebrovascular insults as
assessed by our research will be vulnerable for any insult
or not.
6 | CONCLUSION
COPD nowdays represents a major health problem
worldwide, not only for patients but also for the commu-
nity, so proper prevention and management of COPD
and its exacerbation are now a vital target for a better
quality of life. Systemic inflammation, oxidative stress,
and shared risk factors involved in COPD pathogenesis
should be targeted to prevent serious comorbidities such
as cerebrovascular events. So, early screening of COPD
patients with elevated inflammatory markers, oxidative
burden, and poor lung functions for stroke risk becomes
mandatory and valuable for both patients and the
community.
ACKNOWLEDGMENTS
The authors thank all patients for giving consent for pub-
lication of the data and the control group for contribution
in this research.
16
CONFLICT OF INTEREST
The researchers declared that they have no known com-
peting financial interests or personal relations that could
affect the work reported in this study.
E TH IC S ST A T EME N T
The study protocol was reviewed, was approved by the
research ethics committee of the faculty of medicine, Tanta
University (35 031/11/21), and has therefore been per-
formed in agreement with the ethical standards laid down
in the 1964 Declaration of Helsinki. A comprehensive clari-
fication about the study was given by the researchers after
which they provided consent for publication. All subjects
enrolled in this study gave a written informed consent to
publish the data contained within this study.
A U T H O R S ’ C O N T R I B UT I O N S
Marwa Badr conceptualized the study. Amira Elkholy,
Sara Shoeib, Marwa Bahey, Esraa Mohamed and Alaa
Reda have given inputs in study design. All authors
shared in collecting the data. Marwa Badr analysed the
data and wrote the first draft of the manuscript, and all
co-authors contributed in the critical review of data anal-
ysis and manuscript writing. Marwa Badr acts as the
guarantor for this paper. All authors have read and
approved the manuscript.
C O M PL I A N C E W I T H E T H I C A L
S TA N D A RD S
All ethical standards were maintained. Any unexpected
hazards that appeared during the research will be clari-
fied to the subjects and the ethical committee on time.
There were adequate measures to keep the privacy of par-
ticipants and confidentiality of the data.
DATA AVAILABILITY STATEMENT
Regarding sharing materials, data will be available on
request to the authors.
ORCID
Marwa Y. Badr https://orcid.org/0000-0002-9819-9753
Sara M. Shoeib https://orcid.org/0000-0002-2751-2896
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SU PP O R TI N G I N F O RMA TI O N
Additional supporting information can be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Badr MY, Elkholy AA,
Shoeib SM, Bahey MG, Mohamed EA, Reda AM.
Assessment of incidence of cerebral vascular
diseases and prediction of stroke risk in chronic
obstructive pulmonary disease patients using
multimodal biomarkers. Clin Respir J. 2023;1‐18.
doi:10.1111/crj.13587