Applied Neuropsychology: Adult

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Neuropsychiatric and cognitive symptoms in

people with hypertension: An examination with
the NINDS-CSN consensus protocol

Yen-Hsuan Hsu, Meng Lee, Kuo-Li Pan, Chen-Yu Chen, Tai-Hsin Hung &
Vincent Chin-Hung Chen

To cite this article: Yen-Hsuan Hsu, Meng Lee, Kuo-Li Pan, Chen-Yu Chen, Tai-Hsin Hung
& Vincent Chin-Hung Chen (2024) Neuropsychiatric and cognitive symptoms in people
with hypertension: An examination with the NINDS-CSN consensus protocol, Applied
Neuropsychology: Adult, 31:1, 39-47, DOI: 10.1080/23279095.2021.1986826

To link to this article: https://doi.org/10.1080/23279095.2021.1986826

Published online: 16 Oct 2021.

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APPLIED NEUROPSYCHOLOGY: ADULT
2024, VOL. 31, NO. 1, 39–47
https://doi.org/10.1080/23279095.2021.1986826

Neuropsychiatric and cognitive symptoms in people with hypertension: An

examination with the NINDS-CSN consensus protocol
Yen-Hsuan Hsua,b , Meng Leec,d
, Kuo-Li Pand,e,f
, Chen-Yu Chena, Tai-Hsin Hunge,g,h‡, and
Vincent Chin-Hung Chene,g‡
a
Department of Psychology, National Chung Cheng University, Chiayi, Taiwan; bCenter for Innovative Research on Aging Society (CIRAS),
National Chung Cheng University, Chiayi, Taiwan; cDepartment of Neurology, Chang Gung Memorial Hospital, Chiayi, Taiwan; dDivision of
Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan; eSchool of Medicine, Chang Gung University, Taoyuan, Taiwan; fHeart Failure
Center, Chang Gung Memorial Hospital, Chiayi, Taiwan; gDepartment of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan;
h
Chang Gung Institute of Technology, Taoyuan, Taiwan

ABSTRACT KEYWORDS
Hypertension has been associated with risk of cognitive impairments. The American Heart Hypertension; cognitive
Association recommended the use of the harmonized neuropsychological protocol suggested by function; neuropsycho-
the National Institute of Neurologic Disorders and Stroke and the Canadian Stroke Network logical tests; vascular
cognitive impairment
(NINDS-CSN) for studying related cognitive impairments. Initially designed for vascular cognitive
impairment, empirical data of results from NINDS-CSN protocol has not been well-established in
hypertension. The present study recruited 58 adults diagnosed with hypertension and 44 normo-
tensive controls. Tests from the NINDS-CSN protocol were given in three lengths, including neuro-
psychological tests and neuropsychiatric inventories. The results showed higher proportions of
hypertensive adults with impairments on tests of memory and executive functions and that they
performed worse as a group on several tests from the 30-minute protocol, but not on the other
additional tests in the full-length version, nor on cognitive screening test in the 5-minute protocol
such as the Mini-Mental State Examination or the Montreal Cognitive Assessment. There was no
significant group difference on neuropsychiatric symptoms. These findings suggested that the 30-
minute version of the NINDS-CSN protocol with the two supplemental tests was able to reveal
selective cognitive deficits in hypertensive adults and provide a practical solution for related stud-
ies, balancing between the requirement of sensitivity, domain variety, and brevity.

Introduction subsequent years, and those without proper treatment may

Vascular cognitive impairment (VCI) has been coined to
encompass all types of cognitive disorders resulting from
cerebrovascular diseases with various severity, from mild
cognitive impairment to dementia (Hachinski & Bowler,
1993). Hypertension is one of the major modifiable risk fac-
tors shared by cerebrovascular diseases (Iadecola et al.,
2016), posing a threat to cognitive health by itself.
Hypertensive-related cognitive impairment has been
observed as executive dysfunction and psychomotor slowing
(Harrington et al., 2000; Kuo et al., 2004; Vicario et al.,
2005), while impairment of memory function has also been
reported (Harrington et al., 2000; Saxby et al., 2003; Vicario
et al., 2005). In a case-control study of 105 consecutive
amnestic mild cognitive impairment (MCI), a direct associ-
ation was found between cognitive deficits and vascular risk
factors including arterial hypertension (Casado Naranjo et
al., 2015; Ganguli et al., 2013). Hypertensive people were 2.8
times more likely to have cognitive impairment in
have an even higher risk (Sharifi et al., 2011; Tzourio et al.,
1999). A four-year longitudinal study confirmed the role of
hypertension as a risk factor for mild cognitive disorder in
people in their 60 s (Cherbuin et al., 2009). Overall, the rela-
tionship between hypertension and cognitive impairment
has been consistent in middle-aged population while the
results were equivocal in older patients (Walker et al., 2017).
A recent scientific statement from the American Heart
Association pointed out that there was no standardized cog-
nitive assessment across studies, resulting in inconsistent use
of test tools and diverging evaluation of cognitive domains
in hypertension research (Iadecola et al., 2016). In 2006, the
National Institute of Neurologic Disorders and Stroke and
the Canadian Stroke Network (NINDS-CSN) recommended
the harmonized use of a standardized cognitive test battery
for VCI (Hachinski et al., 2006), including 5-minute, 30-
minute, and 60-minute versions of the protocol. Previous
studies have provided empirical support that all versions of
the NINDS-CSN protocol were valid in assessing VCI

CONTACT Vincent Chin-Hung Chen cch1966@gmail.com; Tai-Hsin Hung davethedr@cgmh.org.tw School of Medicine, Chang Gung University,
Taoyuan, Taiwan.

Meng Lee and Kuo-Li Pan contributed equally.
‡Tai-Hsin Hung and Vincent Chin-Hung Chen contributed equally.
ß 2021 Taylor & Francis Group, LLC
40 Y.-H. HSU ET AL.
Table 1. The neuropsychological test protocols adopted in the present study.
Executive function
Semantic fluency
Digit symbol substitution
Trail Making Test A & B (TMT-A & TMT-B)
Character fluency
Language function
Boston Naming Test (BNT)
Visuospatial function
Rey-Osterrieth Complex Figure Test (RCFT) - Copy
Memory function
Chinese Version Verbal Learning Test (CVVLT)
Neuropsychiatric symptoms
Neuropsychiatric Inventory (NPI, 12-item version)
Center for Epidemiologic Studies Depression Scale (CES-D)
Dementia Screening Tests
Mini-Mental State Examination (MMSE)
Montreal Cognitive Assessment (MoCA)
Other tests
Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE)
†
Indicates the supplemental test.
among stroke patients (Chen et al., 2015; Lin et al., 2016).
This harmonized battery was suggested by the American
Heart Association for future studies concerning impact of
hypertension on cognitive function (Iadecola et al., 2016).
However, the clinical utility of this protocol in hypertension
population has not been examined in empirical studies.
Therefore, the present study aimed to examine the applic-
ability of the NINDS-CSN neuropsychological protocol in a
cohort of hypertensive patients and to examine if the
NINDS-CSN protocol is sensitive to the milder form of VCI
that excludes dementia.
Materials and methods
Participants
Eligible participants were patients diagnosed with hyperten-
sion from outpatient clinics in a teaching hospital and
normotensive volunteers recruited from communities, aged
above 50 years old who gave written informed consent.
From January 2019 to June 2020, 65 hypertensive patients
and 47 normotensive participants were included. A total of
58 hypertensive and 44 normotensive participants completed
the tests and entered the final analysis. Two hypertensive
participants were excluded due to diagnosis of depressive
disorders. Another five hypertensive participants were
excluded due to suspected dementia: Mini-Mental Status
Examination (MMSE, Shyu & Yip, 2001) score lower than
24. The average age of the participants was 62.5 (SD ¼ 7.27)
in the hypertensive group and 60.45 (SD ¼ 7.04) in the
normotensive group. The diagnostic criteria of hypertension
were blood pressure >140/90 mm Hg (Chiang et al., 2015)
at office visit and/or on three occasions throughout their
clinical history, or if they have been taking antihypertensive
medication. Overall, all participants in our study were taking
at least one type of anti-hypertensives, in which 61.2% of
them were taking calcium channel blockers (CCB), 46.4%
taking angiotensin receptor blockers (ARB), 35.3% taking
b-Blockers, 33.4% taking diuretics with ARB, 29.6%
60-Minute 30-Minute 5-Minute
 
 
 †
 


 
 
 
 †


vasodilator, 13% b-Blockers with a-Blockers, 11.2% ARB
with CCB, 3.8% with diuretics, 3.7% Angiotensin-convert-
ing-enzyme inhibitors and 3.7% a-Blockers. Regarding
chronicity, the average duration of diagnosis was 8.9 years
(SD ¼ 6.55, range: 027 years). Regarding comorbidity, 17
hypertensive participants also had hyperlipidemia (29.3%)
and 19 had diabetes mellitus (32.8%). The inclusion criteria
for normotensive volunteers were blood pressure <140/
90 mmHg and scored more than 24 on MMSE. Exclusion
criteria were known stroke history, diagnosis of major psy-
chiatric or neurological disorders (such as dementia, major
depression, substance use disorder, and traumatic brain
injury), severe hearing or visual impairment, movement dis-
turbances, and a score below 24 on MMSE. The project was
approved by the institutional review board in the Chiayi
Chang Gung Memorial Hospital (IRB No. 201801329B0).
Test protocol
According to the NINDS-CSN harmonized consensus
(Hachinski et al., 2006), three versions of cognitive test pro-
tocols with different length (60, 30, and 5 minutes) were rec-
ommended for VCI studies. Neuropsychological tests
adopted in the present study are shown in Table 1.
The 5-minute protocol originally consisted of three indi-
vidual test items of the Montreal Cognitive Assessment
(MoCA; Nasreddine et al., 2005). We administrated the
whole test because a previous study (Dong et al., 2016)
showed that the full MoCA outperformed the subtotal scores
in predicting VCI.
The 30-minute protocol included the Semantic Fluency
(we adopted animal fluency in 30 seconds); Character
Fluency (we adopted a substitute that was based on the
grapheme-based Chinese language for the original phonemic
fluency task; Hung et al., 2016); Digit Symbol Substitution
subtest of the Wechsler Adults Intelligence Scale - the Third
Edition (WAIS-III, Wechsler, 2002); Chinese Version Verbal
Learning Test (Chang et al., 2010) which is a parallel form
of the short form of the California Verbal Learning Test

(The Hopkins Verbal Learning Test was not used due to the
lack of local psychometric data); Center for Epidemiologic
Studies-Depression Scale (CES-D; Radloff, 1977);
Neuropsychiatric Inventory (NPI; Cummings et al., 1994).
The 30-minute protocol also included two supplemental
tests: the MMSE (Shyu & Yip, 2001) and Trail Making Test
(Reitan, 1958) in which the alphabets used in the Trail
Making Test B were substituted as the Chinese
zodiac animals.
The 60-minute protocol included all the tests in the 30-
minute protocol and the additional short form of Boston
Naming Test-2 (Kaplan et al., 1983); the Rey-Osterrieth
Complex Figure Copy (Meyers & Meyers, 1995); and the
Informant Questionnaire for Cognitive Decline in the
Elderly (IQCODE; Jorm et al., 1989). The two supplemental
tests in the 30-minute version, MMSE and Trail Making
Test, were mandatory in this version.
Statistical analysis
Demographic data was compared between the hypertensive
and normotensive groups with independent t-tests or Chi-
square tests, where appropriate. Point-biserial correlational
analyses were conducted to examine the relationships
between sex and test results to determine potential covari-
ates. Independent t tests were then used to compare cogni-
tive test results. Regarding measures that showed significant
correlation with sex, logistic regressions were used to inspect
the relationship after parceling out the influence of sex.
Hierarchical regression analyses were performed to further
examine the influence of hyperlipidemia and diabetes melli-
tus on hypertension-related cognitive dysfunction, control-
ling for age and education. Partial correlation coefficients
were used to estimate the relationship between duration of
hypertension and cognitive function, controlling for age and
education. In order to investigate the effect of age on hyper-
tension-related cognitive impairment, we divided the partici-
pants into the older (60 years) and younger (<60 years)
groups, and examined the performance differences between
hypertensive and normotensive groups using independent t-
tests. Missing values were noted in a few tests (Trail Making
Test-B: 1; CES-D: 3; NPI: 3; and IQCODE: 36). The large
amount of missing data for IQCODE was because hyperten-
sive patients tended to visit the clinics alone, and some of
them or their informants refused to receive additional phone
interview to complete the questionnaire. To test for clinical
significance of cognitive impairments and to delineate the
types of cognitive impairment, frequency of cognitive defi-
cits was calculated for each test and defined as 1.5 standard
deviation (SD) below means of the normotensive group. The
percentage of patients showing cognitive deficit on at least
one test within each cognitive domain was calculated.
Results
There was no significant difference between groups on age
or education (Table 2; age, t(100) ¼ 1.39, p ¼ .167, d ¼ 0.28;
education, t(100) ¼ 1.01, p ¼ .316, d ¼ 0.20). However,
APPLIED NEUROPSYCHOLOGY: ADULT 41
there were more males in the hypertensive group (40 out of
58) than that in the normotensive group (16 out of 44; v2(1)
¼ 11.96, p ¼ .001, u ¼ 0.34). Point-biserial correlational
coefficients indicated that sex was significantly correlated
with some test variables including anxiety and irritability
symptoms on the NPI (Anxiety, r(100) ¼ 0.21, p ¼ .038;
Irritability, r(100) ¼ 0.22, p ¼ .033). Thus, sex was used as
a covariate in the subsequent analyses for these variables.
The independent t-tests (Table 2) revealed that the hyper-
tensive group performed significantly worse than the
normotensive group on the Digit Symbol Substitution, t(100)
¼ 2.39, p ¼ .019, d ¼ 0.48), Trail Making Test part A,
t(100) ¼ 2.28, p ¼ .025, d ¼ 0.46), the immediate recall total
scores, t(100) ¼ .28, p ¼ .005, d ¼ 0.57) and the 30-second
short delayed recall, t(100) ¼ 2.10, p ¼ .038, d ¼ 0.42) of
the Chinese Version Verbal Learning Test. Cohen’s d
showed moderate to large effect size.
After controlling for age and education, multiple regres-
sion showed that performance on the Digit Symbol
Substitution in the hypertensive group could not be
explained by hyperlipidemia (B ¼ 4.71, p ¼ .161) or diabetes
mellitus (B ¼ 2.81, p ¼ .396; DR2 ¼ 0.030, p ¼ .188), nor
could performance on Trail Making Test part A (hyperlipid-
emia: B ¼ 12.08, p ¼ .193; diabetes mellitus: B ¼ 8.30, p ¼
.366; DR2 ¼ .030, p ¼ .349), immediate recall total scores
(hyperlipidemia: B ¼ 0.37, p ¼ .816; diabetes mellitus: B
¼ 0.82, p ¼ .301; DR2 ¼ 0.005, p ¼ .864), or 30-second
short-delay recall (hyperlipidemia: B ¼ 0.04, p ¼ .940; dia-
betes mellitus: B ¼ 0.22, p ¼ .681; DR2 ¼ 0.003, p ¼ .918).
Regarding the effect of chronicity, partial correlation con-
trolling for age and education revealed no significant rela-
tionship between duration of diagnosis and any score on
cognitive tests (jrj ¼ 0.22  0.01, p ¼ .105  .927).
When dividing the participants into younger (60 years)
and older (>60 years) groups, the results showed that in the
middle-aged, younger group, there was a significant differ-
ence between sex (18.2% male in hypertensive group; 53.6%
male in normotensive controls; v2(1) ¼ 5.38, p ¼ .020,
u ¼ 0.36) but not in age (t(39) ¼ 0.08, p ¼ .934, d ¼ 0.03) or
education (t(39) ¼ 1.25, p ¼ .220, d ¼ 0.39). Independent t-
tests showed significant difference between hypertensive and
normotensive groups on the Trail Making Test A (t(39) ¼
2.04, p ¼ .048, d ¼ 0.64) and immediate recall total scores of
the Chinese Version Verbal Learning Test (t(39) ¼ 2.04, p
¼ .048, d ¼ 0.62), and a trend of difference on the Digit
Symbol Substitution (t(39) ¼ 1.86, p ¼ .070, d ¼ 0.58).
Hierarchical logistic regression showed that after controlling
for sex (b ¼ 1.66, SE ¼ 0.77, Wald’s v2 ¼ 4.71, p ¼ .03,
OR ¼ 0.19 [CI: 0.04  0.85]), there were marginal contribu-
tions of Trail Making Test A (b ¼ 0.08, SE ¼ 0.04, Wald’s v2
¼ 3.42, p ¼ .064, OR ¼ 1.08 [CI: 1.00  1.17]) and immedi-
ate recall total scores (p ¼ .071; OR ¼ 0.83 [CI: 0.68  1.02])
to the group assignment. There was no significant contribu-
tion of the Digit Symbol Substitution (p ¼ .095; OR ¼ 0.96
[CI: 0.91  1.01]) to group assignment after controlling for
sex. In the older group, there was a significant difference
between sex (54.5% male in hypertensive group; 79.5% male
in normotensive controls; v2(1) ¼ 4.21, p ¼ .040, u ¼ 0.26)
42 Y.-H. HSU ET AL.

Table 2. Summary of demographic variables and cognitive performance.

t Test
Hypertension participants Normotensive controls
Mean (SD) Mean (SD) t p d
Age (years) 62.45 (7.27) 60.45 (7.04) 1.39 .167 0.28
Education (years) 10.07 (3.23) 10.73 (3.32) 1.01 .316 0.20
Handedness (RH: LH: BH) 58: 0: 0 43: 0: 1
Systolic blood pressure 139.00 (13.83) 126.11 (14.14) 4.62 <.001
0.92
Diastolic blood pressure 82.28 (9.57) 78.52 (10.41) 1.89 .062 0.38
Executive function
Semantic fluency 8.52 (1.64) 8.89 (1.43) 1.19 .237 0.24
DSS 53.48 (15.54) 60.95 (15.78) 2.39 .019
0.48
TMT-A 54.40 (33.50) 42.07 (14.55) 2.28 .025
0.46
TMT-B 109.90 (51.82) 94.77 (49.18) 1.48 .142 0.30
Character fluency 13.69 (14.18) 18.39 (16.27) 1.55 .123 0.31
Language function
BNT (short-form) 9.16 (2.68) 9.23 (2.52) 0.14 .891 0.03
Visuospatial function
RCFT
Copy 34.15 (2.46) 33.72 (5.17) 0.56 .578 0.11
Immediate recall 15.47 (7.26) 16.11 (6.80) 0.46 .647 0.09
Delayed recall 15.10 (7.20) 15.72 (6.46) 0.45 .652 0.09
Memory function
CVVLT
Immediate recall total scores 23.88 (5.40) 26.61 (3.90) 0.28 .005

0.57
30-Second delayed recall 6.67 (1.82) 7.36 (1.38) 2.10 .038
0.42
Short-term retention rate 0.88 (0.18) 0.89 (0.13) 0.12 .904 0.06
10-Minute delayed recall 6.48 (2.07) 7.02 (1.69) 1.41 .162 0.28
Long-term retention rate 0.85 (0.21) 0.84 (0.17) 0.20 .846 0.05
Dementia Screening Tests
MMSE 27.55 (1.14) 27.34 (1.46) 0.82 .415 0.16
MoCA 25.50 (2.62) 25.64 (2.62) 0.26 .795 0.05
Informants’ report†
IQCODE 3.55 (2.49) 3.10 (0.27) 1.06 .293 0.07

p < .05;

p < .01; †30 responses from informants of hypertension participants and 36 responses from informants of the normotensive group;
DSS indicates Digit Symbol Substitution subtest of the Wechsler Adults Intelligence Scale – the Third Edition (WAIS-III); TMT-A: Trail Making
Test A; TMT-B: Trail Making Test B; BNT: Boston Naming Test; RCFT: Rey-Osterrieth Complex Figure Copy Test; CVVLT: Chinese Version Verbal
Learning Test; NPI: Neuropsychiatric Inventory; CES-D: Center for Epidemiologic Studies Depression Scale; MMSE: Mini-Mental State
Examination; MoCA: Montreal Cognitive Assessment; CASI: Cognitive Abilities Screening Instrument; IQCODE; Informant Questionnaire for
Cognitive Decline in the Elderly.

but not in age (t(59) ¼ 0.10, p ¼ .924, d ¼ 0.026) or educa-
tion (t(39) ¼ 0.07, p ¼ .942, d ¼ 0.02). Independent t-tests
showed no significant difference between groups, but only a
marginal group difference on the short-delay recall of the
Chinese Version Verbal Learning Test (t(39) ¼ 1.95, p ¼
.056, d ¼ 0.54). Logistic regression showed that after control-
ling for sex (b ¼ 1.32, SE ¼ 0.63, Wald’s v2 ¼ 4.48, p ¼
.03, OR ¼ 0.27 [CI: 0.08  0.91]), there was significant con-
tribution of short-delay recall of the Chinese Version Verbal
Learning Test (b ¼ 3.65, SE ¼ 1.46, Wald’s v2 ¼ 6.29, p ¼
.048, OR ¼ 0.68 [CI: 0.47  0.997]).
Figure 1 indicates the frequency of cognitive deficits in
the hypertensive group. Twenty-three patients (39.7%)
showed executive dysfunction and 21 patients (36.2%) had
memory impairment. There were also eight and five patients
showing visuospatial (13.8%) and language (8.6%) impair-
ments, respectively. There were 35 out of 58 patients
(60.3%) with cognitive deficits on at least one test scores.
Regarding the number of cognitive domains that were
affected, 19 patients (54.3%) showed deficit in one cognitive
domain, and 11 (31.4%), 4 (11.4%) and 1 (2.9%) patients in
two, three, and four cognitive domains, respectively.
Regarding emotional and behavioral symptoms (Table 3),
there was no significant difference between groups on the
ratings of depressive symptoms on the CES-D, t(97) ¼ 0.03,
p ¼.974, d ¼ 0.01, or other symptoms on the NPI (jt(97)j
¼ 0.88  0.11, p ¼ .38  .91). To examine the confounding
effect of sex, hierarchical logistic regression with group
assignment (hypertensive vs. normotensive) as dependent
variable was performed. Sex first entered Model 1 and sub-
sequently the additional test score entered Model 2.
Regarding the anxiety scores, the results remained non-sig-
nificant (b ¼ 0.36, SE ¼ 0.53, Wald’s v2 ¼ 0.46, p ¼ .50,
OR ¼ 1.43 [CI: 0.51  4.05]) after controlling for sex (b ¼
1.61, SE ¼ 0.45, Wald’s v2 ¼ 12.82, p ¼ < .001, OR ¼ .20
[CI: 0.08  0.48]; Cox and Snell R2 ¼ 0.13; Nagelkerke R2 ¼
0.18). Regarding the irritability scores, the results also
remained non-significant (b ¼ 0.54, SE ¼ 0.47, Wald’s v2 ¼
1.31, p ¼ .25, OR ¼ 0.25 [CI: 0.68  4.36]) after controlling
for sex (b ¼ 1.66, SE ¼ 0.45, Wald’s v2 ¼ 13.58, p ¼ <
.001, OR ¼ 0.19 [CI: 0.08  0.46]; Cox and Snell R2 ¼ 0.14;
Nagelkerke R2 ¼ 0.19).
Discussion
The present study aimed to investigate the clinical utility of
the NINDS-CSN neuropsychological protocol in hyperten-
sion using a case-control study design. The results showed
that the 30-minute protocol captured selective cognitive
impairments associated with hypertension with better time
efficiency than the full-length 60-minute protocol, while the
5-minute protocol that constitutes of cognitive screening
tools did not show expected sensitivity to cognitive
 APPLIED NEUROPSYCHOLOGY: ADULT 43

Figure 1. Percentage of patients with cognitive impairment in different cognitive domains. DSS: Digit Symbol Substitution; TMTA: Trail Making Test part A; TMTB:
Trail Making Test part B; BNT: Boston Naming Test; RCFT: Rey Complex Figure Test; CVVLT: Chinese Version Verbal Learning Test.

Table 3. Emotional and behavioral symptoms between the hypertensive and normotensive groups.
t Test
Hypertensive participants Normotensive controls
Mean (SD) Mean (SD) T p d
CES-D 7.98 (8.53) 7.93 (7.10) 0.03 .974 0.006
NPI (severity
frequency)
Delusions 0.02 (0.13) 0.05 (0.31) 0.63 .531 0.13
Hallucinations 0.02 (0.13) 0 (0) 0.88 .384 –
Agitation/Aggression 0 (0) 0 (0) – – –
Depression/Dysphoria 0.27 (0.73) 0.23 (0.72) 0.24 .810 0.06
Anxiety 0.11 (0.41) 0.12 (0.39) –0.11 .911† 0.02
Euphoria 0 (0) 0 (0) – – –
Apathy 0 (0) 0 (0) – – –
Disinhibition 0 (0) 0 (0) – – –
Irritability 0.11 (0.56) 0.07 (0.34) 0.39 .701† 0.09
Aberrant motor disturbance 0.05 (0.40) 0.02 (0.15) 0.47 .639 0.10
Sleep/Night-time behaviors 0.70 (1.56) 0.56 (1.45) 0.45 .653 0.09
Appetite/Eating 0.29 (0.93) 0.23 (0.87) 0.29 .772 0.07
†
Non-significant after controlling for sex. CES-D indicates the Center for Epidemiologic Studies-Depression Scale; NPI indicates
Neuropsychiatric Inventory.

impairments in hypertension. Memory and executive func-
tions were the most affected cognitive domains in hyperten-
sion, while there was no remarkable neuropsychiatric
manifestation in our hypertensive participants as compared
to normotensive controls.
The 60-minute NINDS-CSN protocol was designed for
studies with interest to tease apart cognitive abilities into
different domains, including executive/activation, language,
visuospatial, and memory domains. Evaluation of neurobe-
havioral change was also included in this protocol. The
30-minute protocol was extracted from the full-length proto-
col and designed as a screening instrument. The 5-minute
protocol was recommended as beside brief screening tool
for primary care physicians. Our results showed that mul-
tiple tests in the 60- and the 30-minute protocols were able
to reflect cognitive impairments of memory, attention-execu-
tive function and psychomotor speed in the hypertension
group, including the list learning test, the Trail Making Test,
and the Digit Symbol Substitution. However, the 60-minute
protocol did not provide incremental value as the additional
Rey-Complex Figure Test and IQCODE did not demonstrate
sensitivity to our hypertensive participants. Meanwhile, the
5-minute protocol was unable to capture the patients’ cogni-
tive impairment unless a supplementary Trail Making Test
was also administrated.
Comparisons of the three versions of the NINDS-CSN
protocol have been conducted among stroke and/or demen-
tia patients in previous studies. Kennedy et al. (2014) dem-
onstrated that the 5-minute protocol was sufficient to
discriminate people with and without stroke in a popula-
tion-based study. Lim et al. (2017) also reported that the 5-
minute protocol revealed significant performance difference
between individuals with and without post-stroke dementia.
However, Xu et al. (2016) examined a less specific
44 Y.-H. HSU ET AL.
participant group, and found that even though the 30-
minute protocol was as good as the 60-minute version in
detecting dementia, the 5-minute one showed similar sensi-
tivity only in individuals with lower education. In Jaywant
et al.’s (2018) study on stroke patients, they adopted the 30-
minute protocol and found that the Symbol Digit Modality
Test, which is similar to the Digit Symbol Substitution in
the present study, was the most sensitive to post-stroke cog-
nitive impairment, even in patients who appeared normal
on MoCA. This is partly consistent to our study, in which
the 5-minute protocol was not sensitive enough for the
hypertensive participants with relatively subtle cognitive
impairment, and in which the Digit Symbol Substitution
demonstrated some sensitivity to hypertension, although not
as much as the list learning test. Overall, the 30-minute
protocol appeared to be more suitable for testing cognitive
disorders in hypertension due to its clinical sensitivity and
time efficiency. Therefore, we are in agreement with Han et
al.’s (2014) view that the 30-minute protocol showed clinical
feasibility with a wide range of cognitive information and
offered a solution for clinical settings that do not allow for a
more comprehensive neuropsychological testing.
Hypertension is generally considered a risk factor of MCI
(Casado Naranjo et al., 2015; Cherbuin et al., 2009; Ganguli
et al., 2013; Luck et al., 2010). In a case-control study of 105
consecutive individuals with amnestic MCI, a direct associ-
ation was found between MCI and arterial hypertension
(Casado Naranjo et al., 2015). However, studies also
reported association between hypertension and non-amnes-
tic MCI (Ganguli et al., 2013). Villeneuve et al. (2009) found
that vascular factors were associated with executive function
impairment in people with amnestic MCI. The population-
based Sydney Memory and Aging Study recruited 757 non-
demented community-welling individuals aged 70 to 90 and
discovered that non-amnestic MCI was more common in
women with hypertension (Sachdev et al., 2012). In line
with previous studies, the present results showed that hyper-
tension affected both memory and executive functions.
Nonetheless, when inspecting the pattern of memory per-
formance, the hypertensive participants as a group only per-
formed worse on the immediate recall but not on the long-
delay recall phase. Thus, it was more likely that the learning
process, rather than the retention process, was compro-
mised. This pattern indicates that the dysexecutive function
observed in our hypertensive patients may in turn affect
other cognitive performance through deficient concept for-
mation or strategy use. The relationship between hyperten-
sion and memory impairment was not consistent in the
literature. Some studies reported selective impairment of
executive function with relatively spared memory ability
(Gottesman et al., 2014; Kuo et al., 2004). The component(s)
and process(es) that were affected by hypertension also have
not been clarified. Vicario et al. (2005) reported both
impaired immediate and delayed recall among hypertensive
participants. However, although Harrington et al. (2000)
found slowed response in both immediate and delayed word
recognition tests in hypertensive participants, defective
accuracy was only noted during delayed word recognition.
In Wolf et al.’s (2007) study, hypertension was associated
with either immediate or delayed memory performance in
verbal or visual memory task, depending on the presence of
central obesity. Furthermore, Ihle et al. (2018) examined the
influence of cognitive reserve, and found that when consid-
ering the effect of education, occupation and leisure time
activities, the impact of hypertension no longer existed on
either immediate or delayed recall performance. Therefore,
it awaits future study to elucidate the nature of memory
problems in hypertension.
The present study did not show a full-blown dysexecutive
syndrome in our hypertensive participants as indicated in
literatures (Gottesman et al., 2014; K€ohler et al., 2014; Reitz
et al., 2007). de Menezes et al.’s (2021) study has shown
similar finding of a lack of relationship between hyperten-
sion and the Trail Making Test B. It is likely that the hyper-
tensive patients in our study have been under well
medication control (systolic and diastolic blood pressure was
139.00 and 82.28 on average, respectively), thereby showing
a more preferable cognitive outcome. Indeed, previous stud-
ies have shown that hypertension treatment was related to
cognitive status (de Menezes et al., 2021; Naing & Teo,
2020). Nonetheless, it is still recommended to explore the
utility of incorporating additional executive function tests in
studies of hypertension, such as the Stroop, Wisconsin Card
Sorting, or prospective memory tests.
The present results showed significant associations
between hypertension and cognitive impairment in both
younger and older hypertensive groups. Walker et al. (2017)
concluded that the relationship between hypertension and
cognitive impairment is less consistent among patients older
than 80, which indicates a “U- or J-shaped” relationships.
However, the participants in our study were aged between
50 and 81, with only one patient older than 80. This may
explain the reason why there was a linear relationship in
our sample. Similar findings of hypertension-related cogni-
tive impairment regardless of age have also been reported in
previous studies with younger samples (de Menezes et al.,
2021; Farron et al., 2020). Interestingly, de Menezes et al.
found that hypertension was associated with cognitive
decline in different domains in middle-age hypertension
(55 years; global cognition and the memory domain) as
compared to late hypertension (<55 years: memory domain).
This is somewhat in accordance to our finding of worse
immediate memory recall (before sex-adjusted), executive
function (i.e. Trail Making Test A) and processing speed
(i.e. Digit Symbol Substitution; before sex-adjusted) in the
middle-aged younger hypertensive group (60 years), while
worse memory performance (i.e. short-delay recall) in the
older hypertensive group even after being adjusted for sex.
The pathology underlying hypertension-related cognitive
impairment has not been clearly elucidated. Some research-
ers proposed that severe atherosclerosis may induce cerebral
hypoperfusion, ischemia, and hypoxia in the brain (Iadecola,
2014; Obisesan, 2009; Qiu et al., 2005; Tadic et al., 2016).
These atherosclerosis-related changes in small or large ves-
sels then induce imbalance in autoregulation of cerebral
blood flow, causing cerebral vascular alterations and

disruption of neurovascular coupling. These functional and
structural changes eventually compromise cognitive capaci-
ties and facilitate neurodegenerative process. Morphological
changes have also been observed in hypertension, where
smaller volume of prefrontal cortex and pathological frontal
white matter changes were evident (Raz et al., 2003, 2007).
This is consistent with the findings that hypertension-related
cognitive impairments involved frontal-related executive
function in our study and in previous reports (Jacobs et al.,
2013; Vicario et al., 2005). It also explains the observation in
our study that the memory impairment merely manifested
in the immediate recall phase that largely relies on frontal-
related encoding and learning abilities, instead of hippocam-
pal-related consolidation processes.
There are several limitations in the present study. First,
the sample size was relatively small, and the sex ratio was
not matched between the hypertensive and normotensive
groups. We performed sensitivity analyses using hierarchical
logistic regression after ANOVA to examine the potential
influence of sex. Second, the current analysis did not include
neuroimaging data. Thus, the relationship between cognitive
dysfunction and brain pathology could not be established by
the present study. Third, we did not analyze the influence of
severity of hypertension on cognitive impairments, which
awaits future studies to investigate. Furthermore, the clinical
history of the normotensive group was based on self-reports.
Thus, comorbidities such as elevated lipid could be potential
confounding factors that led to a more favorable cognitive
picture of the current hypertensive group. In addition, the
additional IQCODE in the 60-minute protocol had a large
amount of missing values, which statistically jeopardizes our
conclusion of favoring the use of the 30-minute protocol.
However, this also implies that the IQCODE may have
some limit for clinical use in outpatient hypertensive
patients since they mostly maintain functional independence
and there would be difficulty in obtaining the informants’
rating. Lastly, blood pressure was not measured uniformly
among all participants. Some were obtained from medical
charts within three months of cognitive assessment, while
others were recorded at the same day of cognitive assess-
ment by a trained research assistant. However, the relation-
ship between blood pressure and cognition was not the
main interest of the present study and it awaits future
research to explore.
In sum, the present study demonstrated that the 30-
minute protocol proposed by the NINDS-CSN may be the
most practical version for hypertensive studies, balancing
between the requirement of sensitivity, domain variety and
time efficiency.
Acknowledgments
We thank all the participants for contributing to this study.
Disclosure statement
No potential conflict of interest was reported by the author(s).
APPLIED NEUROPSYCHOLOGY: ADULT 45
Funding
This work was supported by the Chiayi Chang Gung Memorial
Hospital (CMRPG6I0051; CMRPG6K0191), and partly supported by a
grant from the Ministry of Science and Technology, Taipei, Taiwan
(MOST 107-2410-H-194-066), and the Center for Innovative Research
on Aging Society (CIRAS) from The Featured Areas Research Center
Program within the framework of the Higher Education Sprout Project
by Ministry of Education (MOE) in Taiwan.
ORCID
Yen-Hsuan Hsu http://orcid.org/0000-0002-2585-3339
Meng Lee http://orcid.org/0000-0002-7491-0571
Data availability statement
The data that support the findings of this study are available on
request from the corresponding authors. The data are not publicly
available due to information that could compromise the privacy of
research participants.
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