Clinical Neurology: Research Article
Eur Neurol
DOI: 10.1159/000504704
Hypertension with Hyperhomocysteinemia
Increases the Risk of Early Cognitive Impairment
after First-Ever Ischemic Stroke
Zhen-Hui Lu a, b Jia Li b Xin-Ling Li b Mei Ding b Cheng-Jie Mao a
Xiang-Yang Zhu b Chun-Feng Liu a
a Department
of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, China;
b Department
of Neurology, Second Affiliated Hospital of Nantong University, Nantong, China
Keywords
Cognitive impairment · Hypertension ·
Hyperhomocysteinemia · Ischemic stroke
Abstract
Background: Hypertension and hyperhomocysteinemia
(HHcy) are independent risk factors of stroke and are associ-
ated with each other. Although evidence suggests that they
are related to cognitive impairment, the relationship be-
tween hypertension accompanied with HHcy and post-
stroke cognitive impairment (PSCI) is unclear. Objective: To
define the relationship between hypertension with HHcy
and early cognitive impairment after acute cerebral infarc-
tion. Materials and Methods: Our study enrolled 232 pa-
tients with acute first-ever ischemic stroke. Patients were as-
signed to 3 groups by blood pressure and homocysteine
(Hcy) levels: hypertension with HHcy, simple hypertension,
or control. Cognition was assessed by the Montreal cognitive
assessment at admission and at 3- and 6-month follow-ups.
Results: The hypertension with HHcy group exhibited the
highest incidence of early cognitive impairment (simple hy-
pertension: p = 0.000; control: p = 0.000). This group also had
lower visual space/executive scores than the simple hyper-
tension group (p = 0.000) and lower delayed recall scores
than the control group (p = 0.011). Multivariate analysis
© 2019 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/ene
Received: August 11, 2019
Accepted: November 10, 2019
Published online: December 11, 2019
showed that hypertension with HHcy (OR 7.797; 95% CI
2.917–20.843; p = 0.000), the level of serum Hcy (OR 1.063;
95% CI 1.109–1.109; p = 0.005), education years (OR 0.797;
95% CI 0.722–0.880; p = 0.000), and Fazekas scale of leuko-
araiosis (OR 1.648; 95% CI 1.239–2.191; p = 0.001) were inde-
pendent influencing factors of early PSCI; however, simple
hypertension (OR 1.183, 95% CI 0.208–6.737; p = 0.850) and
simple HHcy (OR 1.112, 95% CI 0.181–6.810; p = 0.909) were
not. Conclusion: Patients with both hypertension and HHcy
are at an increased risk of early cognitive impairment after
acute first-ever ischemic stroke. © 2019 S. Karger AG, Basel
Introduction
A previous study has shown an acute decline in cogni-
tive function after incident stroke and persistent cogni-
tive decline over years [1]. However, early cognitive im-
pairment (at 3 months after onset) has a greater effect on
neurological recovery than delayed cognitive impairment
thus that deserves our more attention. Cognitive impair-
Chun-Feng Liu
Department of Neurology
Second Affiliated Hospital of Soochow University
1055 Sanxiang Road, Suzhou 215004 (China)
193.51.85.197 - 12/12/2019 5:33:15 PM
E-Mail liuchunfeng @ suda.edu.cn
Université René Descartes Paris 5
Xiang-Yang Zhu
Department of Neurology
Second Affiliated Hospital of Nantong University
6 Haier-xiang North Road, Nantong 226001 (China)
Downloaded by:
E-Mail zhuxxyy @ 163.com
ment after stroke is common. A previous investigation
found that the prevalence of poststroke cognitive impair-
ment (PSCI) in China is approximately 81% while that of
nondementia PSCI is 48.91% and poststroke dementia is
32.05% [2]. PSCI worsens quality of life, slows recovery
of function, and increases mortality. Despite of the prev-
alence of PSCI, cognitive assessment after stroke is often
neglected. Once PSCI progresses to poststroke dementia,
the curative effect will be poor, so it is urgent to recognize
and prevent PSCI.
Hypertension and hyperhomocysteinemia (HHcy) are
independent risk factors of stroke. Evidence suggests they
are also associated with each other [3] and appear to be
related to cognitive impairment [4, 5]. However, no stud-
ies have investigated whether (and by what mechanism)
hypertension accompanied with HHcy is related to PSCI.
In China, the prevalence of hypertension accompanied
with HHcy was estimated at 50.2% among elderly persons
aged ≥60 years [6]. In Chinese patients with first-ever
acute cerebral infarction, this study aimed to explore
whether those with both hypertension and HHcy exhib-
ited earlier cognitive impairment and a higher incidence
of PSCI after stroke than those without hypertension or
HHcy.
Materials and Methods
Study Design and Participants
From April to December 2018 in neurology department of Sec-
ond Affiliated Hospital of Nantong University, 232 patients eligi-
ble for inclusion were enrolled in this study. All patients received
routine treatment of acute cerebral infarction during hospitaliza-
tion and secondary prevention during follow-up and did not use
drugs or rehabilitation training that may affect cognitive function.
Inclusion criteria for participants in this study were the follow-
ing: (1) onset of first-ever acute ischemic stroke within 7 days of
enrollment; (2) the ability to undergo a brain MRI examination to
confirm acute infarct of brain, and (3) willingness to undergo a
cognitive functional examination. Patients were excluded from the
study for the following reasons: (1) preexisting cognitive impair-
ment, and the prestroke functional status was determined by the
IQCODE [7]; (2) anxiety or depression examined by the anxiety/
depression self-rating scale; (3) aphasia or uncooperative patients
who could not perform a cognitive functional examination; (4)
strategic infarction that may affect cognition, such as frontal and
temporal lobe, hippocampus, thalamus, and corpus callosum; (4)
venous/arterial thrombolysis, interventional thrombectomy, or
other cerebral diseases such as tumor and hydrocephalus; (5) ce-
rebral hemorrhage transformation; and (6) recurrence of stroke
during follow-up.
Second Affiliated Hospital of Nantong University Ethics Com-
mittee (2018003) approved our study. All participants or autho-
rized agents signed written informed consent.
2 Eur Neurol
DOI: 10.1159/000504704
Sociodemographic, Clinical, Biochemical, and Neuroimaging
Parameters
The following sociodemographic data were collected for all
participants by electronic medical records at admission: age, gen-
der, level of education, smoking status, alcohol drinking status,
and a history of hypertension, diabetes, and cardiac disease.
We monitored blood pressure during hospitalization and col-
lected fasting venous blood samples within 1 day of hospitaliza-
tion. Homocysteine (Hcy), uric acid, cystatin C, total cholesterol,
triglyceride, HDL-C, LDL-C, C-reactive protein, and lipoprotein
phospholipase 2 were detected. Hypertension was defined as sys-
tolic blood pressure (SBP) > 140 mm Hg and/or diastolic blood
pressure >90 mm Hg for 3 times in a quiet condition 1 week after
onset of stroke or having a history of hypertension. HHcy was de-
fined as Hcy level ≥10 μmol/L [8, 9]. Patients were assigned to
groups by blood pressure and Hcy levels: hypertension with HHcy
group, patients with hypertension and HHcy; simple hypertension
group, patients with hypertension but without HHcy; and control
group, patients without hypertension regardless of Hcy level.
Ischemic stroke was classified by the following the Trial of Org
10172 in Acute Stroke Treatment classification [10] subtypes: large-
artery atherosclerosis, small-artery occlusion, cardioembolism, oth-
er determined cause, and undetermined cause. Cerebral infarction
clinical subtypes were categorized according to the Oxfordshire
Community Stroke Project (OCSP) classification [11]: total anterior
circulation infarction, partial anterior circulation infarction, lacu-
nar cerebral infarction, and posterior circulation infarction.
Brain MRI was performed on a 3.0T Verio MRI system (Verio,
Siemens, Germany), with a 16-channel head coil. The scanning
sequences included diffusion weighted imaging, T1WI, T2WI, T2-
fluid-attenuated inversion recovery, and coronal images of T1WI.
All scans covered the entire brain parenchyma.
The severity of cerebral leukoaraiosis was evaluated by Fazekas
scale based on fluid-attenuated inversion recovery sequence im-
ages of brain MRI [12]. The degree of hippocampal atrophy was
evaluated by medial temporal lobe atrophy (MTA) score based on
the coronal images of brain MRI [13].
Cognitive and Neurological Functional Assessment and
Follow-Up
In our study, the Montreal cognitive assessment (MoCA) was
used to evaluate all participants’ cognition during hospitalization
and at 3 and 6 months after onset. Patients with an MoCA score
less than 26 (if years of education ≤12 years, the final score plus 1)
were considered cognitively impaired. The MoCA is a brief and
effective tool for assessing cognitive function, and its specificity
and sensitivity to detect mild cognitive injury are better than those
of the Mini-Mental State Examination [14]. When the cutoff score
is 26, MoCA has been found to have good specificity and sensitiv-
ity [15].
The National Institutes of Health Stroke Scale (NIHSS) [16]
score was used to assess all participants’ neurological function at
admission. Modified Rankin Scale (mRS) was used to assess neu-
rological prognosis at 3 months after onset. An mRS score ≤2 was
considered a good outcome, and an mRS score >2 was considered
a poor outcome.
After 6 months of follow-up, 19 patients were excluded: 9 pa-
tients were lost to follow-up, 6 patients had cerebral hemorrhage
transformation after stroke, 3 patients had a recurrence of cerebral
infarction, and 1 patient died of severe pneumonia (Fig. 1).
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5
Lu/Li/Li/Ding/Mao/Zhu/Liu
Downloaded by:

Baseline: 232 patients with
first-ever acute ischemic stroke
Follow-up for 6 months
19 patients were excluded:
• Lost to follow-up (n = 9)
• Hemorrhage transformation (n = 6)
• Recurrence of stroke (n = 3)
• Died of pneumonia (n = 1)
213 patients completed study
Fig. 1. Flowchart of study participant selection.
Statistical Analysis
SPSS 19.0 was used to perform the statistical analysis. Differ-
ences in baseline characteristics and neurological prognosis among
the 3 groups were tested by the χ2 test, one-way ANOVA, or Krus-
kal-Wallis test. The incidence of PSCI and MoCA scores among 3
groups were compared by χ2 test or Kruskal-Wallis test. Repetitive
ANOVA was used to analyze the change of MoCA score during
follow-up, and χ2 test was used to analyze the change of PSCI in-
cidence after ischemic stroke during follow-up.
Then, patients were resorted into 1 of 2 groups: PSCI group,
presence of PSCI; and no PSCI group, absence of PSCI. Differ-
ences in baseline characteristics and neurological prognosis be-
tween the PSCI group and the no PSCI group were tested by the χ2
test, Student’s t test, or Mann-Whitney U test. Statistical signifi-
cance was set at a p value <0.05.
Finally, we used logistic regression analysis to explore indepen-
dent influencing factors of early PSCI after first-ever acute isch-
emic stroke.
Results
Clinical Characteristics
Of the 232 patients who were initially enrolled in our
study, 19 were excluded during follow-up and 213 com-
pleted the study. The differences in baseline characteris-
tics (gender, age, years of education, a history of diabetes
mellitus and cardiac disease, smoking status, and alcohol
drinking status, time from onset to admission, uric acid,
total cholesterol, triglyceride, HDL-C, LDL-C, C-reactive
protein, lipoprotein phospholipase 2, OCSP type, loca-
tion, MTA score of hippocampal volume, National Insti-
tutes of Health Stroke Scale score at admission) and prog-
nosis among hypertension with HHcy, simple hyperten-
sion, and control groups were not statistically significant
Hypertension with HHcy Increases the
Risk of Early Cognitive Impairment
(p > 0.05, Table 1). However, the differences in level of
Hcy and cystatin C, the Trial of Org 10172 in Acute Stroke
Treatment subtype, and Fazekas scale of leukoaraiosis
were statistically significant (p < 0.05, Table 1). The hy-
pertension with HHcy group had higher cystatin C levels
than the simple hypertension (p = 0.000) and normal
blood pressure (p = 0.042) groups. The hypertension with
HHcy group had more small-artery occlusion than the
control group (p = 0.028). The hypertension with HHcy
group had a more severe scale of leukoaraiosis than the
control group (p = 0.013).
MoCA Score and Incidence of Early PSCI after
Ischemic Stroke
Repetitive ANOVA showed there were statistically sig-
nificant changes in MoCA scores of all study participants
within 6 months after stroke (Fig. 2). MoCA scores de-
creased within 3 months and then slowly increased at 6
months after stroke. However, no statistically significant
difference was found in the incidence of PSCI during the
follow-up period (Fig. 2).
Incidence of Early PSCI and Cognitive Function at 3
Months after Stroke
As indicated in Table 2, the hypertension with HHcy
group showed a higher incidence of early PSCI than the
simple hypertension (p = 0.000) and control (p = 0. 000)
groups. Participants with both hypertension and HHcy
had lower MoCA scores than those with simple hyperten-
sion. No statistically significant differences were found in
the subscores of naming, language, abstraction, and orien-
tation. However, statistically significant differences were
demonstrated in visual space/executive (p = 0.000), atten-
tion (p = 0.003), and delayed recall (p = 0.034) subscores.
Further comparisons indicated that the hypertension with
HHcy group had lower visual space/executive scores than
the simple hypertension group (p = 0.000) and control
group (p = 0.011) and also had lower attention scores than
the simple hypertension group (p = 0.002) and lower de-
layed recall scores than the control group (p = 0.020).
Correlation between Clinical Characteristics and PSCI
at 3 Months after Stroke
All participants were divided into 2 groups according
to whether they were with or without PSCI at 3 months
after stroke. Comparisons between these 2 groups showed
that participants with PSCI were older and had less years
of education than those without PSCI (p < 0.05; Table 3).
The PSCI group had higher cystatin C and serum Hcy
levels than the no PSCI group (p < 0.05; Table 3). Signifi-
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5
Eur Neurol 3
DOI: 10.1159/000504704
Downloaded by:
Table 1. Baseline clinical characteristics of participants by group

Characteristicsa Hypertension with Simple Control group F value p value

HHcy group hypertension (n = 41) or
(n = 128) group (n = 44) χ2 value

Gender, males, n (%) 86 (67.2) 22 (50.0) 30 (73.2) 5.804 0.055

Age, years 66.3 (11.2) 62.8 (10.0) 65.5 (13.4) 1.487 0.229
Education, years 9.2 (4.1) 9.2 (4.1) 8.3 (4.2) 0.740 0.478
Time from onset to admission, days 2.6 (1.7) 2.7 (2.0) 2.4 (1.7) 0.483 0.618
Diabetes mellitus, n (%) 38 (29.7) 21 (47.7) 13 (31.7) 4.862 0.088
Coronary heart disease, n (%) 13 (10.2) 7 (15.9) 6 (14.6) 1.290 0.525
Atrial fibrillation, n (%) 16 (12.5) 2 (4.5) 2 (4.9) 3.650 0.161
Smoking, n (%) 30 (23.4) 9 (20.5) 8 (19.5) 0.362 0.834
Alcohol drinking, n (%) 22 (17.2) 7 (15.9) 7 (17.1) 0.039 0.981
Homocysteine, μmol/L 16.1 (9.6)b 8.6 (0.9)c 14.5 (13.4) 10.025 0.000
UA, μmol/L 334.1 (98.1) 300.4 (105.2) 307.7 (89.0) 2.473 0.087
Cystatin C, mg/L 1.1 (0.3)b,c 0.9 (0.2) 1.0 (0.3) 9.487 0.000
TC, mmol/L 4.3 (0.9) 4.4 (1.0) 4.1 (1.0) 1.280 0.280
TG, mmol/L 1.9 (1.4) 2.0 (1.1) 1.6 (0.9) 1.358 0.259
HDL-C, mmol/L 1.2 (0.3) 1.2 (0.3) 1.2 (0.2) 0.032 0.968
LDL-C, mmol/L 2.7 (0.8) 2.8 (0.9) 2.6 (0.8) 0.514 0.599
CRP, mg/L 4.4 (3.8) 5.2 (5.0) 3.9 (3.5) 1.092 0.337
Lp-PLA2, ng/mL 131.0 (110.7) 116.2 (104.8) 143.2 (118.1) 0.635 0.531
TOAST type, n (%) 16.893 0.010
Large-artery atherosclerosis 38 (29.7)c 17 (38.6) 21 (51.2)
Small-artery occlusion 83 (64.8)c 26 (59.1) 17 (41.5)
Cardioembolism 7 (5.5) 0 3 (7.3)
Other determined cause 0 1 (2.3) 0
OCSP type, n (%) 7.160 0.128
TACI 0 0 0
PACI 34 (26.6) 12 (27.3) 13 (31.7)
LACI 60 (46.8) 19 (43.2) 10 (24.4)
POCI 34 (26.6) 13 (29.5) 18 (43.9)
Location, n (%) 4.511 0.341
Left side 59 (46.1) 18 (40.9) 19 (46.3)
Right side 61 (47.7) 25 (56.8) 17 (41.5)
Bilateral 8 (6.2) 1 (2.3) 5 (12.2)
Fazekas scale of leukoaraiosis, median (IQR) 3 (2)c 2 (2) 2 (2) 7.091 0.029
MTA score of hippocampal volume, median (IQR) 1 (1) 1 (1) 1 (1) 0.808 0.668
NIHSS score 3.7 (2.8) 3.6 (2.8) 3.3 (2.7) 0.328 0.721
Good outcome, n (%) 94 (73.4) 38 (86.4) 36 (87.8) 5.714 0.057
a Data
are expressed as mean (SD) unless otherwise noted.
b p
value <0.05 for comparisons with the simple hypertension group.
c p value <0.05 for comparisons with the control group.

UA, uric acid; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, high-density lipoprotein
cholesterol; CRP, C-reactive protein; Lp-PLA2, lipoprotein phospholipase 2; TOAST, the Trial of Org 10172 in Acute Stroke Treatment;
OCSP, Oxfordshire Community Stroke Project; TACI, total anterior circulation infarction; PACI, partial anterior circulation infarction;
POCI, posterior circulation infarction; LACI, lacunar cerebral infarction; IQR, interquartile range; MTA, medial temporal lobe atrophy;
NIHSS, National Institutes of Health Stroke Scalect.

cant difference in OCSP type was identified between the
2 groups, and the PSCI group had more partial anterior
circulation infarction than the control group (p < 0.05;
Table 3). Participants with PSCI had higher incidences of
hypertension and hypertension with HHcy than those
without PSCI. In addition, patients with PSCI had higher
Fazekas scale and MTA scores than patients without PSCI
(p < 0.05; Table 3). Furthermore, participants without
PSCI had a better prognosis at 3 months after stroke than
those with PSCI (p < 0.05; Table 3).
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5

4 Eur Neurol Lu/Li/Li/Ding/Mao/Zhu/Liu

DOI: 10.1159/000504704
Downloaded by:
 100 35
PSCI MoCA

90 30

80 25

Incidence of PSCI, %

MoCA score, point

70 20
24.03 (5.05) 23.66 (5.05) 23.81 (5.09)
60 15
Fig. 2. Changes in MoCA scores and early
PSCI incidence after ischemic stroke. AA, 50 10
53.1
at admission. There were statistically sig-
nificant changes in MoCA scores (Fb = 46.5
40 5
21.454; pb = 0.000), but no statistically sig- 41.3
nificant change in the incidence of PSCI
(χ2a = 5.919, pa = 0.052). PSCI, poststroke 30 0
AA 3m 6m
cognitive impairment; MoCA, Montreal
cognitive assessment.

Table 2. Comparison of MoCA score and the incidence of PSCI at 3 months after stroke among patients with both hypertension and
HHcy, with simple hypertension and without hypertension

Characteristicsa Hypertension with Simple Control group F value p value

HHcy group hypertension (n = 41) or
(n = 128) group (n = 44) χ2 value

PSCI, n (%) 86 (67.2)b,c 13 (29.5) 14 (34.1) 25.914 0.000

MoCA scores, mean (SD) 22.7±4.8b 25.6±4.3 24.5±5.8 6.042 0.003
Visual space/executive 3 (2)b,c 5 (1.75) 4 (2) 21.787 0.000
Naming 3 (0) 3 (0) 3 (0) 0.424 0.809
Attention 4.5 (3)b 5 (1) 5 (1) 11.653 0.003
Language 3 (1) 3 (1) 3 (0.5) 0.639 0.727
Abstraction 2 (0.75) 2 (0) 2 (0) 0.387 0.824
Delayed recall 3 (4)c 4 (2) 4 (1) 6.736 0.034
Orientation 6 (1) 6 (1) 5 (1) 3.358 0.187
a
 Data expressed as median (interquartile range) unless otherwise noted.
b p value <0.05 for comparisons with the simple hypertension group.
c p value <0.05 for comparisons with the control group.

MoCA, Montreal cognitive assessment; PSCI, poststroke cognitive impairment; HHcy, hyperhomocysteinemia.

Independent Influencing Factors of Early PSCI at 3
Months after Ischemic Stroke
In multivariate logistic regression, we found both hy-
pertension (OR 4.841; 95% CI 1.921–12.196; p = 0.001)
and the level of serum Hcy (OR 1.063; 95% CI 1.109–
1.109; p = 0.005) were independent risk factors of early
PSCI after adjusting for the factors with p < 0.1 in a uni-
variate logistic regression (Table 4, Model 1). Then we
replaced the factors (hypertension and Hcy level) in
Model 1 with the factor (grouping [normal blood pres-
sure, simple hypertension, and hypertension with HHcy])
and found that hypertension with HHcy (OR 7.797; 95%
CI 2.917–20.843; p = 0.000) was an independent risk fac-
tor of early PSCI after ischemic stroke with normal blood
pressure group as the reference while simple hyperten-
sion (OR 1.097, 95% CI 0.345–3.495; p = 0.875) was not
(Table 5, Model 2). Furthermore, we divided normal
blood pressure group in Model 2 into normal blood pres-
sure and Hcy group and simple HHcy group in Model 3
and found that hypertension with HHcy (OR 8.453; 95%
CI 1.542–46.347; p = 0.014) was an independent risk fac-
tor of early PSCI with normal blood pressure and Hcy
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5

Hypertension with HHcy Increases the Eur Neurol 5

Risk of Early Cognitive Impairment DOI: 10.1159/000504704
Downloaded by:
Table 3. Comparison of clinical characteristics between participants with and without PSCI

Characteristicsa PSCI No PSCI t value, p value

(n = 113) (n = 100) U value, χ2

Gender, males, n (%) 67 (59.3) 71 (71.0) 3.188 0.074

Age, years 68.7 (9.1) 61.7 (12.8) −4.587 0.000
Education, years 7.7 (4.6) 10.4 (3.1) 5.156 0.000
Time from onset to admission, days 2.5 (1.6) 2.6 (1.9) 0.372 0.710
Hypertension, n (%) 99 (87.6) 73 (73.0) 7.286 0.007
Homocysteine, μmol/L 15.5 (10.1) 12.8 (9.5) –2.050 0.042
Diabetes mellitus, n (%) 36 (31.9) 36 (36.0) 0.407 0.529
Coronary heart disease, n (%) 10 (8.8) 16 (16.0) 2.531 0.112
Atrial fibrillation, n (%) 12 (10.6) 8 (8.0) 0.428 0.513
Smoking, n (%) 22 (19.5) 25 (25.0) 0.944 0.331
Alcohol drinking, n (%) 16 (14.2) 20 (20.0) 1.289 0.256
UA, μmol/L 324.5 (100.1) 319.2 (97.5) –0.387 0.699
Cystatin C, mg/L 1.1 (0.3) 1.0 (0.2) –2.863 0.005
TC, mmol/L 4.3 (1.0) 4.3 (0.9) –0.115 0.909
TG, mmol/L 1.8 (1.3) 2.0 (1.2) 0.804 0.422
HDL-C, mmol/L 1.2 (0.3) 1.1 (0.3) –1.435 0.153
LDL-C, mmol/L 2.7 (0.8) 2.7 (0.8) 0.459 0.647
CRP, mg/L 4.5 (4.0) 4.4 (4.0) –0.091 0.928
Lp-PLA2, ng/mL 133.8 (112.2) 126.3 (109.5) –0.496 0.621
Grouping 1, n (%) 25.914 0.000
Hypertension with HHcy 86 (76.1) 42 (42.0)
Simple hypertension 13 (11.5) 31 (31.0)
Normal blood pressure 14 (12.4) 27 (27.0)
Grouping 2, n (%) 25.943 0.000
Hypertension with HHcy 86 (76.1) 42 (42.0)
Simple hypertension 13 (11.5) 31 (31.0)
Simple HHcy 10 (8.8) 20 (20.0)
Normal blood pressure and Hcy 4 (3.6) 7 (7.0)
TOAST type, n (%) 2.796 0.424
Large-artery atherosclerosis 45 (39.8) 31 (31.0)
Small-artery occlusion 63 (55.8) 63 (63.0)
Cardioembolism 5 (4.4) 5 (5.0)
Other determined cause 0 1 (1.0)
OCSP type, n (%) 7.274 0.026
TACI 0 0
PACI 40 (35.4) 19 (19.0)
LACI 41 (36.3) 48 (48.0)
POCI 32 (28.3) 33 (30.0)
Location, n (%) 1.572 0.456
Left side 47 (41.6) 49 (49.0)
Right side 57 (50.4) 46 (46.0)
Bilateral 9 (8.0) 5 (5.0)
Fazekas scale of leukoaraiosis, median (IQR) 3 (2) 2 (2) −4.665 0.000
MTA score of hippocampal volume, median (IQR) 1 (1) 0 (1) −3.163 0.002
NIHSS score, mean (SD) 3.8 (2.7) 3.5 (2.9) –0.827 0.409
Good outcome, n (%) 79 (70.0) 90 (90.0) 14.005 0.000
a Dataare expressed as mean (SD) unless otherwise noted.
UA, uric acid; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, high-density lipoprotein
cholesterol; CRP, C-reactive protein; Lp-PLA2, lipoprotein phospholipase 2; TOAST, the Trial of Org 10172 in Acute Stroke Treatment;
OCSP, Oxfordshire Community Stroke Project; TACI, total anterior circulation infarction; PACI, partial anterior circulation infarction;
POCI, posterior circulation infarction; LACI, lacunar cerebral infarction; IQR, interquartile range; MTA, medial temporal lobe atrophy;
NIHSS, National Institutes of Health Stroke Scale; PSCI, post-stroke cognitive impairment.
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5

6 Eur Neurol Lu/Li/Li/Ding/Mao/Zhu/Liu

DOI: 10.1159/000504704
Downloaded by:
Table 4. Risk factors associated with PSCI in multivariate logistic panied with HHcy is an independent risk factor of stroke
regression Model 1 and maybe correlated with PSCI. Recently, the high pro-
portion of Chinese patients with both hypertension and
OR 95% CIs p value
HHcy has been garnering increased attention from cardi-
Hypertension 4.841 1.921–12.196 0.001 ologists and neurologists. Our study showed that patients
Homocysteine 1.063 1.019–1.109 0.005 with both hypertension and HHcy have a higher Fazekas
Education years 0.797 0.722–0.880 0.000 score of leukoaraiosis and an increased incidence of early
Fazekas scale of leukoaraiosis 1.648 1.239–2.191 0.001
PSCI after first-ever acute ischemic stroke. Hypertension
Model 1: Factors (hypertension history, homocysteine, gender, with HHcy was an independent risk factor of early PSCI.
age, education years, Cystatin C, OCSP type, Fazekas scale of leu- In addition, we found that patients with both hyperten-
koaraiosis, and MTA score of hippocampal volume) were included sion and HHcy experience the most severe cognitive im-
in multivariate logistic regression. pairments in visual space/executive, attention, and de-
PSCI, poststroke cognitive impairment; OCSP, Oxfordshire
Community Stroke Project; MTA, medial temporal lobe atrophy.
layed recall functions.
Hcy, an amino acid primarily derived from food, is an
important intermediate of methionine and cysteine me-
tabolism. HHcy participates in the formation of hyper-
Table 5. Risk factors associated with PSCI in multivariate logistic tension, and there is synergy between HHcy and hyper-
regression Model 2 tension. For example, a previous study found that indi-
viduals with hypertension and HHcy are more likely to
OR 95% CIs p value have a stroke [17]. We found that patients with both hy-
pertension and HHcy were more susceptible to small-ves-
Grouping 1
Normal blood pressure 1 (ref.) 0.000 sel cerebral infarction and had the most severe cases of
Simple hypertension 1.097 0.345–3.495 0.875 leukoaraiosis. Also called white matter changes and
Hypertension with HHcy 7.797 2.917–20.843 0.000 white-matter hyperintensity, leukoaraiosis is a clinical
Education years 0.791 0.715–0.876 0.000 syndrome characterized by imaging terms proposed by
Fazekas scale of leukoaraiosis 1.559 1.171–2.077 0.002 Hachinski et al. [18]. Its pathological basis primarily in-
Model 2: Factors (grouping 1 [normal blood pressure, simple cludes loss of the myelin sheath, abnormity of the axon,
hypertension, and hypertension with HHcy], gender, age, educa- arteriosclerosis and lacunar infarction, microinfarction,
tion years, Cystatin C, OCSP type, Fazekas scale of leukoaraiosis, microhemorrhage, and changes in the perivascular sep-
and MTA score of hippocampal volume) were included in multi- tum [19]. Long-term hypertension can damage blood
variate logistic regression. vessels by degrading elastic fibers and increasing cellular/
PSCI, post-stroke cognitive impairment; HHcy, hyperhomo-
cysteinemia; OCSP, Oxfordshire Community Stroke Project; connective tissue components [20, 21]. Arterial stiffness
MTA, medial temporal lobe atrophy. or arteriosclerosis could occlude small perforating arter-
ies, leading to small-vessel lesions [22], and make the self-
regulation of cerebral blood vessels become worse, result-
ing in the brain being more sensitive to hypoperfusion.
group as the reference while simple hypertension (OR White matter is more susceptible to hypoperfusion be-
1.183, 95% CI 0.208–6.737; p = 0.850) and simple HHcy cause its blood supply primarily comes from the water-
(OR 1.112, 95% CI 0.181–6.810; p = 0.909) were not (Ta- shed arteries. Nasrallah et al. [23] also showed that higher
ble 6, Model 3). In the 3 models, it was shown that both SBP caused a larger increase in mean white matter change
of education years and Fazekas scale of leukoaraiosis were volume than lower SBP. However, the data concerning
independent influencing factors of early PSCI. the relationship between HHcy and leukoaraiosis are in-
consistent. Kloppenborg et al. [24] found that HHcy pro-
motes the progression of leukoaraiosis, and Feng et al.
Discussion [25] found that HHcy has a greater effect on cerebral
small vessel disease than large vessel disease. In contrast,
Globally, the prevalence of stroke remains high. A Yu et al. [26] demonstrated that leukoaraiosis is related to
stroke can result in motor and nonmotor disability. The hypertension but not serum Hcy. In our study, we showed
latter has become a research hotspot in the field of neurol- that the combination of hypertension and HHcy had
ogy, especially cognitive function. Hypertension accom- more damage to cerebral white matter and small blood
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5

Hypertension with HHcy Increases the Eur Neurol 7

Risk of Early Cognitive Impairment DOI: 10.1159/000504704
Downloaded by:
 Table 6. Risk factors associated with PSCI in multivariate logistic regression Model 3

OR 95% CIs p value

Grouping 2
Normal blood pressure and Hcy 1 (ref.) 0.000
Simple HHcy 1.112 0.181–6.810 0.909
Simple hypertension 1.183 0.208–6.737 0.850
Hypertension with HHcy 8.453 1.542–46.347 0.014
Education years 0.791 0.714–0.876 0.000
Fazekas scale of leukoaraiosis 1.559 1.171–2.076 0.002

Model 3: Factors (grouping 2 [normal blood pressure and Hcy, simple HHcy, simple hypertension, and hy-
pertension with HHcy], gender, age, education years, Cystatin C, OCSP type, Fazekas scale of leukoaraiosis, and
MTA score of hippocampal volume) were included in multivariate logistic regression.
PSCI, poststroke cognitive impairment; Hcy, homocysteine; HHcy, hyperhomocysteinemia; OCSP, Oxfords-
hire Community Stroke Project; MTA, medial temporal lobe atrophy.

vessels than simple hypertension. Hcy promotes extracel-
lular matrix proliferation [27] and may cause the overex-
pression of matrix metalloproteinase-2 in vascular endo-
thelium that leaded to vascular matrix damage [28]. Hcy
also could increase free oxygen radicals production that
contributed to impaired vascular endothelial function by
oxidative injury [29, 30]. In a study on hypertension by
Guo et al. [31], HHcy was suggested to aggravate oxida-
tive stress, thus promoting vascular impairment. Im-
paired endothelial function of cerebral small vessels re-
sulting in cerebral hypoperfusion and ischemia is expect-
ed to further aggravate white matter leukoaraiosis. Our
study also showed that patients with both hypertension
and HHcy had highest cystatin C levels. Cystatin C is se-
creted from microglia, astrocytes and neurons, and its
level in the brain parenchyma rises as neurons degenerate
[32]. Cystatin C is upregulated in degenerative astrocytes
in a self-defense response to the process of white matter
degeneration [33]. Lee et al. [34] also reported that Cys-
tatin C level was significantly correlated with white-mat-
ter hyperintensity volume. Thus, Cystatin C might be a
mediator in the association between hypertension ac-
companied with HHcy and leukoaraiosis.
This study indicated that hypertension accompanied
with HHcy was an independent risk factor of early PSCI
after first-ever acute ischemic stroke; however, simple hy-
pertension and simple HHcy were not. Our findings fur-
ther support the viewpoint that HHcy and hypertension
have a strong synergistic effect with each other. Hyper-
tension accompanied with Hcy accelerates endothelial
impairment and atherosclerosis, which are major patho-
logical processes in dementia [35]. We also found the lev-
el of serum Hcy was an independent risk factor of early
PSCI while simple HHcy was not. This result is not self-
contradictory, probably due to the low value of HHcy set
in the study. In our future study, we will stratify serum
Hcy at different levels and further explore its association
with PSCI. In addition, education years and Fazekas scale
of leukoaraiosis were independent influencing factors of
early PSCI after ischemic stroke. In a previous study, a
higher education level as a reasonable indicator of knowl-
edge reserves was found to reduce the risk of PSCI, which
is consistent with our findings [36]. Leukoaraiosis has
been suggested as a mediator in the association between
hypertension accompanied with HHcy and PSCI. Stroke
patients with preexisting leukoaraiosis were more vulner-
able to cognitive impairment regardless of the ischemic
lesions [37]. A possible explanation was that widespread
leukoaraiosis impaired cognitive resilience of stroke pa-
tients by diffusive damaging to brain’s network, thus pre-
disposing cognitive impairment once after ischemic
stroke occurred [38]. The mechanism by which leukoara-
iosis causes cognitive impairment is still unclear. Previ-
ous studies have confirmed that cognitive impairment is
correlated with the degree of white matter loss [39] and
remote white matter is related to cognitive function with-
in a long period after ischemic stroke [40]. There is evi-
dence that it may be related to the damage of long joint
fibers that play a role in cognitive function, such as demy-
elination, loss of oligodendrocytes, and axonal injury
[41]. Yuan et al. [42] also provided further evidence that
leukoaraiosis may result in the impairment of subcortical
and cortical-cortical connections and then leading to cog-
nitive dysfunction, especially in executive function.
Further analysis of MoCA subscores indicated that pa-
tients with both hypertension and HHcy have the lowest
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5

8 Eur Neurol Lu/Li/Li/Ding/Mao/Zhu/Liu

DOI: 10.1159/000504704
Downloaded by:
visual space/executive, attention, and delayed recall
scores. Recent studies showed that early cognitive impair-
ment of patients with leukoaraiosis may be most obvious
in visual space/executive function, delayed recall, abstrac-
tion, and orientation [43], and that cerebral small vessel
disease is related to delayed recall dysfunction [44]. The
hippocampus and the cerebral cortex are vulnerable to
ischemia and anoxia [45], which may be a potential mech-
anism of PSCI. It would also explain why patients with
PSCI are most impaired in visual space/executive and de-
layed recall functions.
The prevalence of PSCI increased to 53.1% at 3rd
month and then decreased to 46.5% at 6th month in our
study. The trend of PSCI incidence is consistent with pre-
vious study [46]. However, incidence of PSCI in our study
was lower than previous studies, which perhaps be attrib-
uted to the exclusion of strategic infarction. In addition,
statistically significance changes in MoCA scores were
found within 6 months after stroke. Furthermore, we will
extend the observational time to acknowledge the regu-
larity and characteristics of long-term PSCI after acute
ischemic stroke.
Our study has some limitations. First, only patients
with first-ever ischemic stroke were included while those
who developed venous thrombolysis were excluded.
However, in clinical practice, there will be more and more
patients with several times of stroke, and more and more
patients develop venous thrombolysis, so we can analyze
the factors such as number of strokes and venous throm-
bolysis in the future research. Second, this study did not
involve the correlation between intervention of hyperten-
sion with HHcy and PSCI. Third, other factors that may
be associated with PSCI, such as the level and rhythm of
blood pressure, blood pressure variability, blood glucose,
cerebral microbleed, and obstructive sleep apnea syn-
drome, were not measured in our current study. In future
research, we can include these factors in the analysis.
Conclusion
Hypertension accompanied with HHcy was found to
increase the risk of early PSCI after first-ever acute isch-
emic stroke, especially in visual space/executive, atten-
tion, and delayed recall functions. Patients with PSCI af-
ter first-ever ischemic stroke have worse prognosis at 3
months. Although simple hypertension and simple HHcy
are not independent risk factors of PSCI, hypertension
accompanied with HHcy and the level of serum Hcy are.
This suggests neurologists should pay more attention to
Hypertension with HHcy Increases the
Risk of Early Cognitive Impairment
hypertension accompanied with HHcy and measure se-
rum Hcy routinely in patients with hypertension. Once
acute cerebral infarction occurs in patients with both hy-
pertension and HHcy, we recommend assessing cognitive
function, monitoring the patient closely, and treating
cognitive impairments as soon as possible.
Acknowledgment
I would like to express my gratitude to all those who helped me
during the writing of this thesis. A special acknowledgement
should be shown to Prof. Chun-Feng Liu, from whose lectures I
benefited greatly. I am particularly indebted to Prof. Xiang-Yang
Zhu, who gave me kind encouragement and useful instructions all
through my writing.
Statement of Ethics
The study was approved by Second Affiliated Hospital of Nan-
tong University Ethics Committee (2018003). All participants or
authorized agents signed written informed consent.
Disclosure Statement
The authors have no conflicts of interest to disclose.
Funding Sources
This work was supported by Jiangsu Provincial Medical Key
Discipline Project (ZDXKB2016022) and Suzhou Clinical Re-
search Center of Neurological Disease (Szzx201503).
Author Contributions
Z.-H.L., X.-Y.Z., and C.-F.L. conceived and designed the study.
Z.-H.L., J.-L., X.-L.L., and M.D. performed collection of medical
records and follow-up. Z.-H.L. analyzed the data and wrote the
paper. C.-J.M. and C.-F.L. reviewed and edited the manuscript. All
authors read and approved the manuscript.
References   1 Levine DA, Galecki AT, Langa KM, Unver-
zagt FW, Kabeto MU, Giordani B, et al. Tra-
jectory of cognitive decline after incident
stroke. JAMA. 2015 Jul;314(1):41–51.
  2 Qu Y, Zhuo L, Li N, Hu Y, Chen W, Zhou Y,
et al. Prevalence of post-stroke cognitive im-
pairment in china: a community-based,
cross-sectional study. PLoS One. 2015 Apr;
10(4):e0122864.
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5
Eur Neurol 9
DOI: 10.1159/000504704
Downloaded by:
  3 Virdis A, Ghiadoni L, Cardinal H, Favilla S,
Duranti P, Birindelli R, et al. Mechanisms re-
sponsible for endothelial dysfunction in-
duced by fasting hyperhomocystinemia in
normotensive subjects and patients with es-
sential hypertension. J Am Coll Cardiol. 2001
Oct;38(4):1106–15.
  4 Levine DA, Wadley VG, Langa KM, Unver-
zagt FW, Kabeto MU, Giordani B, et al. Risk
Factors for Poststroke Cognitive Decline: The
REGARDS Study (Reasons for Geographic
and Racial Differences in Stroke). Stroke.
2018 Apr;49(4):987–94.
  5 Smith AD, Refsum H. Homocysteine, B vita-
mins, and cognitive impairment. Annu Rev
Nutr. 2016 Jul;36(1):211–39.
  6 Ma L, Li L, Tang Z. Epidemiological charac-
teristics of hyperhomocysteinemia and H-
type hypertension in the elderly in Beijing,
China. Clin Exp Hypertens. 2017; 39(7): 640–
4.
  7 Park MH. Informant questionnaire on cogni-
tive decline in the elderly (IQCODE) for clas-
sifying cognitive dysfunction as cognitively
normal, mild cognitive impairment, and de-
mentia. Int Psychogeriatr. 2017 Sep; 29(9):
1461–7.
 8 McCully KS. Homocysteine, vitamins, and
vascular disease prevention. Am J Clin Nutr.
2007 Nov;86(5):1563S–8S.
  9 Qin X, Huo Y. H-Type hypertension, stroke
and diabetes in China: opportunities for pri-
mary prevention. J Diabetes. 2016 Jan; 8(1):
38–40.
10 Adams HP Jr, Bendixen BH, Kappelle LJ,
Biller J, Love BB, Gordon DL, et al. Classifi-
cation of subtype of acute ischemic stroke.
Definitions for use in a multicenter clinical
trial. TOAST. Trial of Org 10172 in Acute
Stroke Treatment. Stroke. 1993 Jan; 24(1):
35–41.
11 Bamford J, Sandercock P, Dennis M, Burn J,
Warlow C. Classification and natural history
of clinically identifiable subtypes of cerebral
infarction. Lancet. 1991 Jun;337(8756):1521–
6.
12 Fazekas F, Chawluk JB, Alavi A, Hurtig HI,
Zimmerman RA. MR signal abnormalities at
1.5 T in Alzheimer’s dementia and normal ag-
ing. AJR Am J Roentgenol. 1987 Aug; 149(2):
351–6.
13 Scheltens P, Launer LJ, Barkhof F, Weinstein
HC, van Gool WA. Visual assessment of me-
dial temporal lobe atrophy on magnetic reso-
nance imaging: interobserver reliability. J
Neurol. 1995 Sep;242(9):557–60.
14 Nasreddine ZS, Phillips NA, Bédirian V,
Charbonneau S, Whitehead V, Collin I, et al.
The Montreal Cognitive Assessment, MoCA:
a brief screening tool for mild cognitive im-
pairment. J Am Geriatr Soc. 2005 Apr; 53(4):
695–9.
15 Ciesielska N, Sokołowski R, Mazur E, Pod-
horecka M, Polak-Szabela A, Kędziora-
Kornatowska K. Is the Montreal Cognitive
Assessment (MoCA) test better suited than
the Mini-Mental State Examination (MMSE)
10 Eur Neurol
DOI: 10.1159/000504704
in mild cognitive impairment (MCI) detec-
tion among people aged over 60? Meta-
analysis. Psychiatr Pol. 2016 Oct; 50(5):
1039–52.
16 Goldstein LB, Samsa GP. Reliability of the
National Institutes of Health Stroke Scale.
Extension to non-neurologists in the context
of a clinical trial. Stroke. 1997 Feb;28(2):307–
10.
17 Towfighi A, Markovic D, Ovbiagele B. Pro-
nounced association of elevated serum homo-
cysteine with stroke in subgroups of individu-
als: a nationwide study. J Neurol Sci. 2010
Nov;298(1-2):153–7.
18 Hachinski VC, Potter P, Merskey H. Leuko-
araiosis. Arch Neurol. 1987 Jan;44(1):21–3.
19 Wallin A, Román GC, Esiri M, Kettunen P,
Svensson J, Paraskevas GP, et al. Update on
vascular cognitive impairment associated
with subcortical small-vessel disease. J Al-
zheimers Dis. 2018;62(3):1417–41.
20 Mahmud A, Feely J. Arterial stiffness is relat-
ed to systemic inflammation in essential hy-
pertension. Hypertension. 2005 Nov; 46(5):
1118–22.
21 Sun Z. Aging, arterial stiffness, and hyperten-
sion. Hypertension. 2015 Feb;65(2):252–6.
22 Nam KW, Kwon HM, Jeong HY, Park JH,
Kim SH, Jeong SM, et al. Cerebral white mat-
ter hyperintensity is associated with intracra-
nial atherosclerosis in a healthy population.
Atherosclerosis. 2017 Oct;265:179–83.
23 Nasrallah IM, Pajewski NM, Auchus AP,
Chelune G, Cheung AK, Cleveland ML, et al.;
SPRINT MIND Investigators for the SPRINT
Research Group. Association of intensive vs
standard blood pressure control with cerebral
white matter lesions. JAMA. 2019 Aug;
322(6):524–34.
24 Kloppenborg RP, Geerlings MI, Visseren FL,
Mali WP, Vermeulen M, van der Graaf Y, et
al.; SMART Study Group. Homocysteine and
progression of generalized small-vessel dis-
ease: the SMART-MR Study. Neurology. 2014
Mar;82(9):777–83.
25 Feng C, Bai X, Xu Y, Hua T, Huang J, Liu XY.
Hyperhomocysteinemia associates with small
vessel disease more closely than large vessel
disease. Int J Med Sci. 2013;10(4):408–12.
26 Yu X, Wang G, Zhan J, Zhang Z, Feng T, Xu
J. Risk factors of pure leukoaraiosis and the
association with preclinical carotid athero-
sclerosis. Atherosclerosis. 2018 Aug;275:328–
32.
27 Spence JD. Homocysteine-lowering therapy:
a role in stroke prevention? Lancet Neurol.
2007 Sep;6(9):830–8.
28 Liu J, Jin X, Liu KJ, Liu W. Matrix metallopro-
teinase-2-mediated occludin degradation and
caveolin-1-mediated claudin-5 redistribution
contribute to blood-brain barrier damage in
early ischemic stroke stage. J Neurosci. 2012
Feb;32(9):3044–57.
29 Eikelboom JW, Hankey GJ, Anand SS, Loft-
house E, Staples N, Baker RI. Association be-
tween high homocyst(e)ine and ischemic
stroke due to large- and small-artery disease
but not other etiologic subtypes of ischemic
stroke. Stroke. 2000 May;31(5):1069–75.
30 Tian X, Zhao L, Song X, Yan Y, Liu N, Li T, et
al. Hsp27 inhibits homocysteine-induced en-
dothelial apoptosis by modulation of ros pro-
duction and mitochondrial caspase-depen-
dent apoptotic pathway. BioMed Res Int.
2016;2016:4847874.
31 Guo G, Sun W, Liu G, Zheng H, Zhao J. Com-
parison of oxidative stress biomarkers in hy-
pertensive patients with or without hyperho-
mocysteinemia. Clin Exp Hypertens. 2018;
40(3):262–6.
32 Wada M, Nagasawa H, Kawanami T, Kurita
K, Daimon M, Kubota I, et al. Cystatin C as an
index of cerebral small vessel disease: results
of a cross-sectional study in community-
based Japanese elderly. Eur J Neurol. 2010
Mar;17(3):383–90.
33 Umegae N, Nagai A, Terashima M, Watanabe
T, Shimode K, Kobayashi S, et al. Cystatin C
expression in ischemic white matter lesions.
Acta Neurol Scand. 2008 Jul;118(1):60–7.
34 Lee WJ, Jung KH, Ryu YJ, Kim JM, Lee ST,
Chu K, et al. Cystatin C, a potential marker
for cerebral microvascular compliance, is
­associated with white-matter hyperintensi-
ties progression. PLoS One. 2017 Sep; 12(9):
e0184999.
35 Yarchoan M, Xie SX, Kling MA, Toledo JB,
Wolk DA, Lee EB, et al. Cerebrovascular ath-
erosclerosis correlates with Alzheimer pa-
thology in neurodegenerative dementias.
Brain. 2012 Dec;135(Pt 12):3749–56.
36 Ojala-Oksala J, Jokinen H, Kopsi V, Lehtonen
K, Luukkonen L, Paukkunen A, et al. Educa-
tional history is an independent predictor of
cognitive deficits and long-term survival in
postacute patients with mild to moderate
ischemic stroke. Stroke. 2012 Nov; 43(11):
2931–5.
37 Kliper E, Ben Assayag E, Tarrasch R, Artzi M,
Korczyn AD, Shenhar-Tsarfaty S, et al. Cog-
nitive state following stroke: the predominant
role of preexisting white matter lesions. PLoS
One. 2014 Aug;9(8):e105461.
38 Mok VC, Lam BY, Wong A, Ko H, Markus
HS, Wong LK. Early-onset and delayed-onset
poststroke dementia – revisiting the mecha-
nisms. Nat Rev Neurol. 2017;13(3):148–59.
39 Lampe L, Kharabian-Masouleh S, Kynast J,
Arelin K, Steele CJ, Löffler M, et al. Lesion lo-
cation matters: the relationships between
white matter hyperintensities on cognition in
the healthy elderly. J Cereb Blood Flow Metab.
2019 Jan;39(1):36–43.
40 Schaapsmeerders P, Tuladhar AM, Arntz
RM, Franssen S, Maaijwee NA, Rutten-Jacobs
LC, et al. Remote lower white matter integrity
increases the risk of long-term cognitive im-
pairment after ischemic stroke in young
adults. Stroke. 2016 Oct;47(10):2517–25.
41 Kalaria RN. Neuropathological diagnosis of
vascular cognitive impairment and vascular
dementia with implications for Alzheimer’s
disease. Acta Neuropathol. 2016 May;131(5):
659–85.
193.51.85.197 - 12/12/2019 5:33:15 PM
Université René Descartes Paris 5
Lu/Li/Li/Ding/Mao/Zhu/Liu
Downloaded by:
42 Yuan JL, Wang SK, Guo XJ, Teng LL, Ji- imaging data detects microstructural damage 45 Ishibashi S, Kuroiwa T, LiYuan S, Katsumata
ang  H, Gu H, et al. Disconnections of in mild cognitive impairment and alzheimer’s N, Li S, Endo S, et al. Long-term cognitive and
cortico-subcortical pathways related to
­ disease patients. J Magn Reson Imaging. 2018; neuropsychological symptoms after global
cognitive impairment in patients with
­ 48(3):767–79. cerebral ischemia in Mongolian gerbils. Acta
­leukoaraiosis: A preliminary diffusion tensor 44 van Es AC, van der Grond J, de Craen AJ, Neurochir Suppl (Wien). 2006;96:299–302.
imaging study. Eur Neurol. 2017; 78(1-2): Westendorp RG, Bollen EL, Blauw GJ, et al.; 46 He M, Wang J, Liu N, Xiao X, Geng S, Meng
41–7. PROSPER Study Group. Cerebral micro- P, et al. Effects of blood pressure in the early
43 Giulietti G, Mario T, Laura S, Barbara S, Ca- bleeds and cognitive functioning in the phase of ischemic stroke and stroke subtype
millo M, Carlo C, et al. Whole brain white PROSPER study. Neurology. 2011 Oct; on poststroke cognitive impairment. Stroke.
matter histogram analysis of diffusion tensor 77(15):1446–52. 2018 Jul;49(7):1610–7.

193.51.85.197 - 12/12/2019 5:33:15 PM

Université René Descartes Paris 5

Hypertension with HHcy Increases the Eur Neurol 11

Risk of Early Cognitive Impairment DOI: 10.1159/000504704
Downloaded by: