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Association of carotid artery stiffness with measures of cognition in older adults

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Association of carotid artery stiffness with measures of cognition in older adults

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Content Association of Carotid Artery Stiffness with Measures of Cognition in Older Adults
By
Cindy Zamora
A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTERS OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)
August 2024
Copyright 2024 Cindy Zamora

ii
Acknowledgements
I am grateful for having the opportunity to analyze and work on my thesis in the Master’s
Program. This has been a privilege for me as a first generation college student and I am forever grateful to
everyone who has helped me. I would like to thank Jose-Alfredo and Angelica C. I also thank my
committee and faculty members for allowing me to gain experience and knowledge in the future field I
will pursue.
I look forward to pursuing a higher education and this is my first stepping stone to which I can
look back.

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Table of Contents
Acknowledgements……………………………………………………………………………………..…..ii
List of Tables…………………………………………………………………...……………………….…iv
List of Figures……………………………………………………………………………………………....v
Abstract…………………………………………………………………………………………………….vi
Chapter 1: Introduction……………………………………………………..………………………………1
Chapter 2: Methods………..………………………………………………………………………………..2
Chapter 3: Results……………………………………..……………………………………………………6
Chapter 4: Discussion..……………………………………………………………………………………15
Chapter 5: Conclusion…...………………………………………………………………………………...17
References…………………………………………………………………………………………………18
Appendix…………………………………………………………………………………………………..20

iv
List of Tables
Table 1: Baseline Demographic Information on Study Participants……………..………...……….………8
Table 2: Cross-Sectional Adjusted Association of Common Carotid Artery Distensibility with
Measures of Cognition by Study…………….……………………………………………………………...9
Table 3: Longitudinal Adjusted Association of Common Carotid Artery Distensibility with 2.5
year change in Measures of Cognition by Study……………...………………..…………………………10
Table 4: Spline Analysis for Longitudinal Adjusted Association of Executive Cognitive Function
and Common Carotid Artery Distensibility with a 2.5 year change in ELITE Study (Unadjusted
and Adjusted)…………..………………………………………………….………………………….…...10
Table 5: Cross-Sectional Adjusted Association of Common Carotid Artery Distensibility with
Measure of Cognition by Gender….………………………………………………………………………12
Table 6: Longitudinal Adjusted Association of Common Carotid Artery Distensibility with
2.5 year change in Cognition by Gender………...…………………………………………………….......12
Table 7: Cross-Sectional Adjusted Association of Common Carotid Artery Distensibility with
Measures of Cognition by Time Since Menopause: ELITE and NAPS Women...……………….....……13
Table 8: Longitudinal Adjusted Association of Common Carotid Artery Distensibility with
2.5 year change in Measures of Cognition by Time Since Menopause: ELITE and NAPS Women..……14
Appendix Table 1: Cross-Sectional Unadjusted Associations of Common Distensibility with
Measures of Cognition at Baseline…………………………...………………………………………...…20
Appendix Table 2: Longitudinal Unadjusted Association of Common Distensibility with
2.5 year change in Cognition……………………………...………………………………………………21

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List of Figures
Figure 1: STROBE Figure…………………………………………………………………………………7
Appendix Figure 1: Spline at <19 or greater >19 distensibility…………………..……………………….20

vi
Abstract
Background: Age-related changes in older adults increase their risk for multiple diseases. Specifically,
age is associated with cognitive decline that may lead to Alzheimer’s disease, dementia, and cognitive
impairment. Multiple studies have shown an association between artery stiffness and cognitive
impairment; thus artery stiffness is a potential predictor of cognitive decline. In this study, we aimed to
evaluate the association between artery stiffness and cognitive functions using both cross-sectional and
longitudinal analysis using data from two randomized clinical trials. We additionally conducted analyses
stratified by sex and stage of menopause as possible effect modifiers to further understand the association
between arterial stiffness and cognition.
Methods: We used data from Early vs Later Intervention with Estradiol (ELITE) trial participants, who
were postmenopausal women. We then added Nattokinase Atherothrombotic Prevention Study (NAPS)
trial participants that included postmenopausal women and men. Cognitive composite measures that were
calculated as composite scores from a neuropsychological test battery were assessed as four dependent
cognitive variables – global cognition, verbal memory, visual memory, and executive functions. The main
independent variable was carotid artery distensibility measured at baseline, calculated from carotid artery
ultrasound. Using linear regression, cognition-stiffness associations were assessed at baseline in crosssectional analyses. Associations with changes in cognition from baseline to 2.5-3 years were assessed in
longitudinal analysis. Stratification was evaluated by gender, trial, and early/late menopausal status.
Menopausal status was also tested as an effect modifier to further investigate the stiffness-cognition
associations.
Results: In ELITE, verbal memory was positively associated with carotid distensibility at baseline (beta
(SE) = 0.019 (0.0088); p=0.035); this association was also seen in the combined ELITE and Naps sample.
For the longitudinal change, baseline carotid distensibility was positively associated with change in global
cognition; this association was seen both in NAPS females (beta (SE) = 0.031 (0.014)) and combined
samples (beta (SE) = 0.014 (0.0068)) (p<0.05). In females, only verbal memory was associated with
distensibility at baseline (beta (SE) = 0.020 (0.0088); p=0.024) and with global cognition in the 2.5-3 year

vii
change (beta (SE) = 0.014 (0.0071); p = 0.049). By menopausal status, women in late menopause showed
significant associations of distensibility with all four dependent cognitive domains in the cross-sectional
analysis of baseline measures. For the longitudinal analysis, only changes in global cognition and verbal
memory were positively associated with baseline carotid distensibility in late menopause. For the early
menopause group, there were no significant associations of cognition with distensibility at both baseline
and the 2.5-3 year change. The test for menopause-distensibility interaction was significant only in the
cross-sectional analysis for all four cognitive variables (interaction p<0.046 cross-sectional).
Conclusion: Carotid artery distensibility was positively associated with verbal memory and global
cognition. The results were confined to older women in late menopause. Carotid artery stiffness may help
identify persons at risk for cognitive decline and may also be an avenue for intervention in older persons
and women in late menopause. Further research is needed in this area.

1
Chapter 1: Introduction
From past decades to now, lifespan has increased; by 2030, 1 in 5 Americans will be ages 65 years and
older[4]. Older adults are at risk for multiple age-related chronic diseases, in particular cognitive decline.
Cognitive health is essential for thinking, learning, and memory, which are essential for daily function
[12]. According to the CDC, 5.8 million Americans aged 65 years or older have Alzheimer's Disease in
2020 [3]. By 2060, approximately 14 million people will be living with Alzheimer’s Disease [1,3].
Symptoms usually appear after age 60 [3]. The prevalence of Alzheimer’s disease among adults aged 65
and older is more common in women [1]. Compared to older whites, Alzheimer’s disease is higher in
Blacks/African Americans (14%) and Hispanics (12%) [1]. Cognitive decline is one of the earliest
noticeable traits evident in multiple diseases, including dementia, Alzheimer's disease, stroke, depression,
delirium, and heart disease [4].
In previous studies, carotid artery stiffness has been associated with cognitive impairment and
dementia[14]. The mechanism behind this is that carotid artery stiffness reflects higher pressure in the
brain, which can subsequently impose a greater load and potentially disrupt cerebral microcirculation
[14,15 ]. This process can lead to damage in the low resistance microvascular bed in the brain, ultimately
resulting in cerebral small-vessel disease (CSVD) or other diseases [14]. CSVD markers have been
closely associated with cognitive impairment, including dementia [14]. Thus increased carotid artery
stiffness can help identify individuals at risk for cognitive impairment, dementia, and cerebral smallvessel disease. Identifying patients at higher risk may ensure timely interventions and prevention
strategies for patients with elevated carotid artery stiffness.
The aim of this study is to assess whether baseline measures of carotid artery distensibility are
cross-sectionally associated with cognitive functions in older adult participants of two randomized clinical
trials. Baseline assessment of carotid artery distensibility was also correlated longitudinally with 2.5-3
year changes in cognition. Analyses were stratified by sex, menopausal status (early vs. later
postmenopause), and by study (only including females). Finally, we tested whether menopausal status
(early vs late menopause) was an effect modifier of the association between distensibility and cognition.

2
Chapter 2: Methods
ELITE Study and Participants
The Early vs Late Intervention Trial with Estradiol (ELITE) study was a randomized clinical trial that
investigated whether the effects of oral 17B-estradiol on the progression of early (subclinical)
atherosclerosis and cognitive decline in healthy postmenopausal women differed by time since
menopause [9]. Eligible participants included women with a serum estradiol level of 25 pg/ml or less, no
menstrual period for 6 months or more, and postmenopausal less than 6 years or 10 years or longer. The
primary outcome was the progression of subclinical atherosclerosis, measured as the annual rate of
change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year). CCA was
measured from carotid artery ultrasounds at two baseline examinations and then every 6 months after
randomization over the trial follow-up. Secondary outcomes assessed the change in neurocognitive
function and coronary artery calcium at the end of the trial. The change in neurocognitive function was
measured by neuropsychological test scores completed at baseline and follow up assessments (2.5 years
and 5 years); cognitive outcomes included four cognitive composite scores (global cognition, verbal
memory, visual memory, and executive functions). After the trial, the carotid ultrasound images were
used to measure carotid artery stiffness. The study was approved by the USC Institutional Review Board
and was registered on clinicaltrials.gov (NCT00114517).
NAPS Study and Participants
The Nattokinase Atherothrombotic Prevention Study (NAPS) was a randomized, placebo-controlled
double-blind clinical trial that tested the effectiveness of nattokinase supplementation on carotid
atherosclerosis progression (measured by carotid artery ultrasonography) and cognitive aging [10].
Eligible participants were healthy postmenopausal women (had no uterine bleeding for >6 years) or men;
participants were 55 years and older. The trial lasted for 5 years, with 2 years for recruitment and a
subsequent 3 years of treatment. Carotid ultrasounds were completed at two baseline visits and postrandomization every 6 months until 36 months. The primary outcome was the progression of carotid
artery intima-media thickness (mm per year). Secondary trial outcomes were rate of carotid artery

3
stiffness progression. Another secondary outcome was the change from baseline in global cognition
composite score, verbal memory score, and executive function score that were collected at baseline, 18
months, and 36 months. This study was approved by the University of Southern California Institutional
Review Board and was registered on clinicaltrials.gov (NCT02080520).
Cognitive Measures
The cognitive measures were evaluated as four dependent cognitive variables (a general measure of
global cognition, a measure of verbal memory, a measure of executive cognitive function, and a measure
of visual memory). For the two studies, the cognitive tests (complete test battery) were composed of
Symbol Digit Modalities, Trail Making test (Part B ( Shipley Abstraction, Letter-Number Sequencing,
Block Design, Judgement of Line Orientation (Form H), category fluency (animal naming), Boston
Naming Test, California Verbal Learning Test (immediate and delayed recall), East Boston Memory Test
(immediate and delayed), Faces 1 (immediate recall) and II (delayed recall), Stroop Color and Word Test,
and Benton Visual Retention Test. Cognitive assessments were conducted 3 times in ELITE (at baseline
before randomization, and 2.5- and 5-years after randomization) and 3 times in NAPS (at baseline before
randomization, and 18 and 36 months after randomization). Scores for all cognitive tests were
standardized by the following equation:
The mean score is the trial-specific mean test score calculated at baseline for the entire sample (either
NAPS or ELITE), while the trial-specific standard deviation is the test score at baseline, again for the
entire randomized sample. Cognitive composite outcomes were a weighted average of multiple tests
weighted by the inverse inter-test correlation matrix. A higher score in the assessments means better
cognitive performance. For each cognitive composite score (verbal memory, global cognition, executive
function, and visual memory), the study evaluated the change from baseline by using the endpoint minus
baseline cognitive outcome.

4
Assessment of Carotid Artery Distensibility
Arterial distensibility refers to the stiffness of the arteries located in the neck, with higher values
indicating less stiffness. For each trial, the high resolution B-mode carotid ultrasounds used to measure
the primary trial outcome of common carotid artery intima-media thickness were used to measure carotid
artery diameters. The carotid artery lumen diameters were measured at systole and diastole. Along with
systolic and diastolic blood pressures, the carotid stiffness measures were calculated as:
Arterial Distensibility= [2(DS - DD)/DD]/PP
The units of distensibility are 10-6 N
-1m
2
. The DS and DD, in the equation are the carotid lumen diameters
at systole and diastole, respectively. PP represents a pulse pressure measure that is calculated by
subtracting diastolic from systolic blood pressure.
Statistical Analyses
To test whether carotid artery stiffness (independent variable) was associated with cognition (dependent
variable), associations were tested: (1) cross-sectional associations with both independent and dependent
variables measured at baseline (before randomization), and (2) longitudinal associations of baseline
stiffness measures with 2.5-year change in cognition. For all analysis, LINE assumptions (Linearity,
Independence, Normality, and Homoscedasticity/Equal Variances) were evaluated. This includes
diagnostics on residuals that were examined to evaluate outliers, including evaluation of leverage, Cook's
D, DFFITS, and DFBETAs - normality of residuals. Leverage identifies any observations in which
independent variables differ from the mean of the sample (i.e., the distance of the specific x-value from
the mean of all the X values (independent variables)). Cook’s D, DFBETAS, and DFFITS are used to
determine the amount of influence an observation might have on the estimated regression slopes. A t-test
was conducted to determine if the Jackknife residual was statistically significant and used in advanced
residual analysis to identify influential points. Sensitivity analyses were performed to evaluate possible
changes in linear regression effect Beta (β) estimates when outliers were removed for both associations.
The first linear regression models used ELITE data at the first baseline visit to test cross-sectional
association between the stiffness of arteries in the neck and measures of cognition (Table 2). We

5
compared the baseline, unadjusted association models to linear regressions adjusted for confounders (that
included age, race, systolic blood pressure, income, education, and body mass index). Influential data
points were identified and changes in regression coefficients when each observation was excluded (i.e.,
impact on the parameter estimates (e.g. intercept, slopes) were evaluated.
We used a spline regression for the model evaluating the association between artery stiffness and measure
of executive cognitive function, given that it was the only one that seemed to not satisfy linearity (Table
4). For the spline regression model, we split the assessment of association into participants that had
distensibility below 19 and above 19 to correlate with 2.5 year change in executive cognitive function.
Executive cognitive functions were also evaluated using the single linear regression slope to compare to
the spline regression model. For the last analysis we tested an interaction to observe if menopausal status
was a potential modifier for distensibility association with a 2.5 year change in cognition (Table 8).
Cognitive associations with carotid distensibility were evaluated at a 0.05 significance level. SAS
software (SAS 9.4) was used for all analyses.

6
Chapter 3: Results
The total sample size from ELITE and NAPS included 907 participants (Figure 1); 642 came from
ELITE and 265 from NAPS. Only one ELITE participant was excluded because they did not have a
baseline cognitive examination.

7
aOnly one person was excluded in the cross-sectional analysis because there was no baseline cognitive examination.
bFor the Longitudinal analysis 111 participants were excluded due to loss to follow-up.
ELITE participants were on average 59.9 years old; NAPS participants were on average 66.2 years old
(Table 1). Females made up 88.86% of the combined sample. The majority of participants were
2166 were telephoned screened for ELITE
1271 were ineligible
895 were clinically screened
252 Were excluded
133 Did not
meet criteria
119 declined to
participate
643 Were randomized
1189 were telephoned screened for NAPS
857 were ineligible
332 were clinically screened
67 Were excluded
51 Did not meet
criteria
16 declined to
participate
265 Were randomized
908 combined entire sample
size
908 Cross Sectional Analysisa
1 excluded
642 in ELITE
265 in NAPS
908 Longitudinal Analysisb
111 excluded
567 in ELITE
230 in NAPS
Figure 1. Entire Sample of Study

8
non-Hispanic white 66.4% ELITE, 70.6% NAPS). Among women, 35.9% were in early menopause (<
6yrs), while 61.7% were in later menopause (>10 years). For income, 1.93% refused to provide income
data. The most common income category was participants making an income greater than $100,000
(33.8%). Participants were in general highly educated with 40.24% self-reporting Graduate/Professional
degrees, and 27.23% reporting having received a Bachelor’s Degree. The overall average (SD) systolic
blood pressure for the combined sample was 117.3(14.72) and 67.3 (8.2) mmHg for diastolic blood
pressure. The overall average body mass index was 27.2 (5.3)kg/m2
.

9

All categorical variables are frequency (%)
All continuous variable are mean (SD)
ELITE SAMPLE (SPLINE INCLUDED)
aAdjusted for covariates: age, race, systolic blood pressure, income , education, and body mass index.
Income was considered continuous.
Table 2 shows adjusted cross-sectional associations of common carotid artery distensibility and measures
of cognition. In unadjusted models, carotid distensibility was statistically significantly positively
associated with cognition (global cognition, verbal memory, executive functions, and visual memory)
(p<0.018). However for adjusted associations only verbal memory was statistically significant. The
estimated change in measure of verbal memory increased by 0.0186 per unit of carotid distensibility
(p=0.035, 95%CI: 0.0013, 0.0358). For the cross-sectional analysis, outliers were not significant. For
global cognition, the outliers were not significant but had a change of effect estimate by 39% and
executive functions had a change in beta coefficient of 25.18%. We retained these outliers because they
were biologically plausible.

10
All Adjusted for covariates: age, race, systolic blood pressure, income , education, and body mass index.
3Combines ELITE & NAP Study, including both Males and Females
Table 3 shows the adjusted associations of common distensibility artery distensibility and 2.5/3-year
change in measures of cognition. The unadjusted positive associations of the carotid artery distensibility
with 2.5-year change were statistically significant in all measures of cognition (p<0.046) except visual
memory (Appendix Table 2). With adjustment for covariates, only the positive association of carotid
distensibility with 2.5-year change in verbal memory was close to the cutoff of being statistically
significant (p=0.069). The estimated adjusted 2.5-year change in verbal memory increases by 0.014 (95%
CI: -0.001, 0.028) per unit change in carotid artery distensibility. The outliers were significant in both 2.5-
year changes in global cognition and verbal memory. The beta coefficient change for global cognition
was 12%, while the beta coefficient change for verbal memory was 10%.
1Adjusted for covariates: age, race, systolic blood pressure, income , education, and body mass index.
For Table 4, a spline regression model was used in the longitudinal analysis for the measure of executive
cognitive function. Table 4 shows the unadjusted and adjusted spline regression for the association of
common carotid artery distensibility (Distensibility ≤19, Distensibility ≥ 19) and the 2.5-year change in
cognition. When observing the spline regression model for the change in the measure of executive
cognitive function and distensibility, there was no significance both for the adjusted and unadjusted
model (p>0.05). This was seen both for distensibility equal to or greater than 19 and distensibility equal to
or less than 19.
NAPS FEMALES

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Among NAPS females, no cognitive measures were cross-sectionally associated with distensibility
(Table 2). Outliers were significant for global measure of cognition and measure of verbal memory.
There was a coefficient change greater than 100% and 17.06%, respectively. For the longitudinal analysis
in NAPS females, only global cognition change was significantly positively associated with distensibility
(Table 3). The regression analysis indicated an average 2.5-year change in the measure of global
cognition increasing by 0.03092 per unit of carotid distensibility (p=0.031, 95% CI: 0.00286, 0.0589).
The only measure that had significant outliers was executive functions; there was a beta coefficient
change of 36.63%.
COMBINED ALL GENDER SAMPLE (ELITE and NAPS)
The unadjusted cross-sectional association models for all measures of cognition and distensibility were all
significant (p<0.007) at baseline (Appendix Table 1). For the adjusted models using the cross-sectional
analysis, we observed statistical significance in verbal memory (Table 2). The estimated change in
measure of verbal memory increased by 0.018 per unit of carotid distensibility (p=0.012, 95% CI: 0.004,
0.032). The association with change in executive functions was of borderline significance (p=0.058).
Measures of executive cognitive function had significant outliers when assessing sensitivity on the
regression model. There was a 25% beta coefficient change.
All longitudinal unadjusted models were statistically significant for the 2.5-year change in cognition with
a p-value less than 0.0036 except visual memory (Appendix Table 2). For the adjusted longitudinal
models, change in global cognition was significantly associated with distensibility (Table 3). The
estimated 2.5-year change in the measure of global cognition increased by 0.014 per unit of carotid
distensibility (p=0.045, 95% CI: 0.0003, 0.0268). The positive longitudinal association with change in
executive functions was of borderline significance (p=0.053). There was a 12% beta coefficient change.
Global measure of cognition, measure of visual memory, and measure of executive functions had
significant outliers.

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STRATIFICATION BY GENDER

1Adjusted for covariates: age, race, systolic blood pressure, income , education, and body mass index.
For females in the baseline cross-sectional analysis, only verbal memory was significantly positively
associated with distensibility (Table 5). Executive functions had a borderline significance (p=0.052). For
females the estimated change in measure of verbal memory increased by 0.019 per unit of carotid
distensibility (p=0.0244, 95% CI: 0.003, 0.037). The beta coefficient change for verbal memory is 37%
with outlier exclusion and global cognition had significant outliers as well. For males, there were no
statistically significant cross-sectional associations between carotid distensibility and any cognitive
composite scores (Table 5). Outliers were significant for global cognition with a beta coefficient change
greater than 100% and executive cognitive functions that were similar.
1Adjusted for covariates: age, race, systolic blood pressure, income , education, and body mass index.
Longitudinal analysis revealed (Table 6) statistically significant positive associations among females
between distensibility and 2.5 year change in global cognition (p=0.049). Among women, the estimated
2.5-year change in the measure of global cognition increased by 0.014 per unit of carotid distensibility
(95% CI: 0.000095, 0.0279). Verbal memory showed a positive association of borderline

13
significance (p=0.061) Among males, no longitudinal associations were statistically significant in any of
the 2.5-year change in measures of cognition and distensibility (Table 6). Outliers in females for global
cognition and measure of executive cognitive functions, had a beta coefficient change of 10% and 18%,
respectively. In males, global cognition had a beta coefficient change of greater than 100%, while for
measures of verbal memory had a beta coefficient change of 100%. Additionally both cognitive measures
had significant outliers.
STRATIFICATION BY MENOPAUSE IN FEMALE COMBINED SAMPLE
Income is considered continuous for all associations.
1Adjusted for covariates: age, race, systolic blood pressure, income , education, and body mass index, including interaction models.
Among the early menopause group, no measures of cognition and distensibility were associated with
distensibility on cross-sectional analysis (Table 7). The early menopause group had significant outliers
for measures of executive at baseline; the beta coefficient was greater than 100%. Statistical significance
was detected among all measures of cognition and distensibility in the late menopause group, with all
cross-sectional associations in the positive direction (Table 7). For the late menopause group, the
estimated change in measure of global cognition increased by 0.060 per unit of carotid distensibility
(p<0.001, 95% CI: 0.033, 0.086). The estimated change in verbal memory increased by 0.040 per unit of
carotid distensibility among the late menopause group (p=0.0002, 95% CI: 0.0193, 0.0615). The
estimated change in executive functions increased by 0.033 per unit of carotid distensibility among the
late menopause group (p=0.0019, 95% CI: 0.0123, 0.0544). In the late menopause group, the estimated
change in visual memory increased by 0.019 per unit of carotid distensibility (p=0.0409, 95% CI:
0.00077, 0.0366). Outliers were significant for both executive function and verbal memory; there was a
18% beta coefficient change in both of these variables. Also, there was evidence for a statistically
significant interaction in cross-sectional associations between menopausal status and distensibility across

14
all measures of cognition (Table 7). This indicated a relationship between all measures of cognition and
distensibility is significantly different between early menopause and late menopause groups.
Income is considered continuous for all associations. .
1Adjusted for covariates: age, race, systolic blood pressure, income, education, and body mass index, including interaction models.
In the longitudinal analysis, no measures of cognitive change were associated with baseline distensibility
in the early menopause group (Table 8). There were significant outliers for global cognition and verbal
memory. Global cognition had a beta change of 19% and verbal memory had a beta change of 98%. In the
later postmenopause group, 2.5-year change in global cognition was significantly positively associated
with baseline distensibility (Table 8). The estimated 2.5-year change in measure of global cognition
increased by 0.02214 per unit of carotid distensibility (p=0.0147, 95% CI: 0.0044, 0.03991). Outliers
were significant for measure of executive cognitive function and measure of visual memory. The beta
coefficient change results in 3% and 81%, respectively. The estimated 2.5-year change in measure of
verbal memory increased by 0.01702 per unit of carotid distensibility (p=0.0491, 95% CI: 0.0001,
0.0340). There was a negative beta coefficient change of 10%.
Only the association of global cognition in changes and distensibility was of borderline significance for
the interaction in menopausal status (Table 8).

15
Chapter 4: Discussion
We used combined data from two randomized clinical trials to test cross-sectional and longitudinal
associations of carotid artery stiffness (distensibility) with global cognition and various cognitive
domains. Analyses adjusted for age, race, systolic blood pressure, income, education, and body mass
index. We observed the following cross-sectional associations in verbal memory across ELITE sample
and combined sample, including stratification in gender and menopause. Relating baseline distensibility
with 2.5/3-year changes in cognition, we observed longitudinal associations in NAPS sample only,
combined all gender sample (ELITE and NAPS), and with stratification by gender.
While we evaluated associations with global cognition and cognitive domains, we primarily observed
distensibility associations with verbal memory and global cognition. Studies have shown that an increase
in carotid artery stiffness is also linked to cognitive impairment and dementia [14]. In a recent 2022
paper, the NINDS-Canadian Stroke Network harmonization neuropsychological battery was used to
assess cognition and found that carotid artery stiffening was associated with global cognition independent
of CSVD [14]. These results are similar to our results that found global cognition to be significantly
associated with carotid artery stiffness in the NAPS as well as the combined longitudinal study, including
in analyses stratified by gender and early/late menopause.
Another study assessed specifically the difference of menopausal status (pre- and post-menopausal
females) between the relation of arterial stiffness and cognitive performances. This study did not find any
statistical difference in associations between the menopause groups, except that post-menopausal females
had a lower performance on a challenging condition of a working memory task [2]. We did find a
significant modification by early/late post-menopause only at baseline cross-sectional analysis. Effect
modification by time since menopause, was not observed in the 2.5-3 year cognitive change.
In other studies, important factors were considered similar to our study, including age, gender, and blood
pressure [8,11,14]. In this study we added adjustment for additional factors (race, income, education,
etc.). Compared to other recent studies, we evaluated measures of cognition as a whole to understand the

16
impact this may have on distensibility. Also an important modifier as menopausal status did have impact
in our study, and in future studies should be considered as well as other factors. This study mainly only
included older people and associations may differ in a younger population.
Limitations
Because the data arose from randomized clinical trials, the study population does not reflect a general
population sample. Generalizability is also limited to older adults. Generalizability would be specific to
older healthy men and women (postmenopausal). The study does not generalize to women of reproductive
age or women in the menopausal transition.

17
Chapter 5: Conclusion
Overall, we observe statistically significant associations of carotid artery stiffness with some measures of
cognition. Menopausal status and gender show some significant results and should be considered as
additional factors when analyzing this association. These are important to consider for stratification in
other studies. There is still need for more research and clinical studies to evaluate the stiffness-cognitive
association altogether and to further understand this possible association. Furthermore, there is statistical
significance showing a possible association between carotid artery distensibility and all four measures of
cognition. Brain health is very important and as we start aging, the brain will age as well. Further future
research in this area may aid in development of early interventions, treatments, and medications. The need
for care for brain health is important especially with an increase in the older population and people living
longer lives.

18
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(2022). A Cross-Sectional Comparison of Arterial Stiffness and Cognitive Performances in
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Appendix
Appendix Figure 1: Spline at <19 or greater >19 distensibility
Appendix Table 1: Cross-Sectional Unadjusted Associations of Common Distensibility with Measures
of Cognition at Baseline
Appendix Table 2: Longitudinal Unadjusted Association of Common Distensibility with 2.5 year change
in Cognition

21

Abstract (if available)

Abstract Background: Age-related changes in older adults increase their risk for multiple diseases. Specifically, age is associated with cognitive decline that may lead to Alzheimer’s disease, dementia, and cognitive impairment. Multiple studies have shown an association between artery stiffness and cognitive impairment; thus artery stiffness is a potential predictor of cognitive decline. In this study, we aimed to evaluate the association between artery stiffness and cognitive functions using both cross-sectional and longitudinal analysis using data from two randomized clinical trials. We additionally conducted analyses stratified by sex and stage of menopause as possible effect modifiers to further understand the association between arterial stiffness and cognition.

Methods: We used data from Early vs Later Intervention with Estradiol (ELITE) trial participants, who were postmenopausal women. We then added Nattokinase Atherothrombotic Prevention Study (NAPS) trial participants that included postmenopausal women and men. Cognitive composite measures that were calculated as composite scores from a neuropsychological test battery were assessed as four dependent cognitive variables – global cognition, verbal memory, visual memory, and executive functions. The main independent variable was carotid artery distensibility measured at baseline, calculated from carotid artery ultrasound. Using linear regression, cognition-stiffness associations were assessed at baseline in cross-sectional analyses. Associations with changes in cognition from baseline to 2.5-3 years were assessed in longitudinal analysis. Stratification was evaluated by gender, trial, and early/late menopausal status. Menopausal status was also tested as an effect modifier to further investigate the stiffness-cognition associations.

Results: In ELITE, verbal memory was positively associated with carotid distensibility at baseline (beta (SE) = 0.019 (0.0088); p=0.035); this association was also seen in the combined ELITE and Naps sample. For the longitudinal change, baseline carotid distensibility was positively associated with change in global cognition; this association was seen both in NAPS females (beta (SE) = 0.031 (0.014)) and combined samples (beta (SE) = 0.014 (0.0068)) (p<0.05). In females, only verbal memory was associated with distensibility at baseline (beta (SE) = 0.020 (0.0088); p=0.024) and with global cognition in the 2.5-3 year change (beta (SE) = 0.014 (0.0071); p = 0.049). By menopausal status, women in late menopause showed significant associations of distensibility with all four dependent cognitive domains in the cross-sectional analysis of baseline measures. For the longitudinal analysis, only changes in global cognition and verbal memory were positively associated with baseline carotid distensibility in late menopause. For the early menopause group, there were no significant associations of cognition with distensibility at both baseline and the 2.5-3 year change. The test for menopause-distensibility interaction was significant only in the cross-sectional analysis for all four cognitive variables (interaction p<0.046 cross-sectional).

Conclusion: Carotid artery distensibility was positively associated with verbal memory and global cognition. The results were confined to older women in late menopause. Carotid artery stiffness may help identify persons at risk for cognitive decline and may also be an avenue for intervention in older persons and women in late menopause. Further research is needed in this area.

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Creator Zamora, Cindy (author)

Core Title Association of carotid artery stiffness with measures of cognition in older adults

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Degree Conferral Date 2024-08

Publication Date 06/20/2024

Defense Date 06/20/2024

Publisher Los Angeles, California (original), University of Southern California (original), University of Southern California. Libraries (digital)

Tag artery stiffness,carotid,cross-sectional analysis,executive function,global cognition,longitudinal analysis,measures of cognition,OAI-PMH Harvest,older adults,verbal memory,visual memory

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