Hypertension Research

https://doi.org/10.1038/s41440-023-01419-3

ARTICLE

Special Issue: Current evidence and perspectives for hypertension management in Asia

Associations for progression of cerebral small vessel disease burden

in healthy adults: the Kashima scan study
Toshihiro Ide1 Yusuke Yakushiji1,2 Kohei Suzuyama1 Masashi Nishihara3 Makoto Eriguchi1 Atsushi Ogata4
● ● ● ● ● ●

Akiko Matsumoto5 Megumi Hara6 Hideo Hara1

● ●

Received: 29 April 2023 / Revised: 4 August 2023 / Accepted: 5 August 2023

© The Author(s), under exclusive licence to The Japanese Society of Hypertension 2023

Abstract
To investigate the association between vascular risk factors and progression of cerebral small vessel disease (SVD), we
conducted a longitudinal study with neurologically healthy cohort composed mostly of middle-aged adults (n = 665, mean
age, 57.7 years). Subjects, who had both baseline data of brain health examinations including MRI and follow-up MRI at
least 1 year after the baseline MRI, were included this study. The presence of features of SVD, including lacunes, cerebral
microbleeds, white matter hyperintensity, and basal ganglia perivascular spaces were summed to obtain “total SVD score”
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(range, 0–4). Progression of SVD was evaluated among subjects with a total SVD score of ≤ 3 and was defined as a ≥ 1 point
increase in that score at follow-up relative to baseline. As the primary analysis, multivariate logistic regression analyses were
performed to determine the associations of progression of SVD at baseline. The median follow-up period was 7.3 years and
progression of SVD was observed in 154 subjects (23.2%). Even after adjustment with confounders multivariate logistic
regression analyses showed that progression of SVD was associated with age (per 10-year increase, odds ratio [OR]: 2.08,
95% confidence interval [CI] 1.62–2.67), hypertension (OR 1.55, 95%CI 1.05–2.29), systolic blood pressure (BP) (per
standard deviation [SD] increase, OR 1.27, 95%CI 1.04–1.54), diastolic BP (per SD increase, OR 1.23, 95%CI 1.01–1.50),
and mean arterial pressure (per SD increase, OR 1.27, 95%CI 1.04–1.55). Age and high blood pressure appear to play key
roles in the progression of cerebral small vessel burden after mid-life.
Keywords Age Blood pressure Cerebral small vessel burden Hypertension Smoking
● ● ● ●

Introduction

Sporadic cerebral small vessel disease (SVD) is the most

Supplementary information The online version contains
common age-related pathological process of the arteries,
supplementary material available at https://doi.org/10.1038/s41440-
023-01419-3. arterioles, venules, and capillaries of the brain caused by
vascular risk factors related to vasculopathy or endothelial
* Yusuke Yakushiji dysfunction, and plays an important role in the development
yakushiy@hirakata.kmu.ac.jp
of stroke and dementia [1]. Effective prevention of such
1
Division of Neurology, Department of Internal Medicine, Saga common geriatric brain diseases requires a better under-
University Faculty of Medicine, Saga, Japan standing of the pathogenesis and mechanisms of asympto-
2
Department of Neurology, Kansai Medical University, matic SVD progression from mid-life to old age. It is still
Hirakata, Japan difficult to directly observe cerebral micro vessels in vivo,
3
Department of Radiology, Saga University Faculty of Medicine, but advances in understanding of age-related MRI findings
Saga, Japan in the brain allow us to non-invasively estimate small vessel
4
Department of Neurosurgery, Saga University Faculty of burden [1–3]. These findings (i.e., SVD biomarkers) include
Medicine, Saga, Japan lacunes, cerebral microbleeds (CMBs), white matter
5
Department of Social Medicine, Saga University Faculty of hyperintensity (WMH), and perivascular space (PVS),
Medicine, Saga, Japan which often coexist and relate to each other [4]. The concept
6
Department of Preventive Medicine, Saga University Faculty of of total SVD score is based on SVD biomarkers and has
Medicine, Saga, Japan recently been proposed as a comprehensive index of SVD

Graphical Abstract
Point of view
● Clinical relevance
Cerebral small vessel disease (SVD) worsened in
one in five (23.2%) neurologically healthy adults
(mainly in midlife) during long-term follow-up
(median 7.3 years) and age and hypertension were
related to progression of SVD burden.
● Future direction
A prospective interventional study to test that
management of mid-life hypertension might be the
most important target for preventing sporadic global
SVD progression in old age is warranted.
● Consideration for the Asian population
SVD with type 1 pathology [age-related or vascular
risk factor-related] has been reported to be more common
in Asian population than in Western population.
T. Ide et al.
severity in the brain [5]. Several cross-sectional studies have
revealed associations between various vascular risk factors
and total SVD score [5–7]. Moreover, higher total SVD
score was associated with increased risk of cere-
brocardiovascular events [8]. However, little is known
regarding the factors that affect serial change in total SVD
burden. The aim of this study was to investigate the asso-
ciation of demographic characteristics, vascular risk factors,
and clinical findings in mid-life with the subsequent pro-
gression of SVD in neurologically healthy adults.
Methods
Design and setting
The Kashima Scan Study is a cohort study that included
Japanese individuals who received an optional “brain
health examination” and has the objective of investigating
Associations for progression of cerebral small vessel disease burden in healthy adults: the Kashima. . .
age-related brain changes using MRI of the brain in neu-
rologically healthy adults [9, 10]. The study was performed
and reported with reference to the Strengthening the
Reporting of Observational Studies in Epidemiology
guidelines [11].
Subjects
Among 1729 consecutive adults who underwent the brain
health examinations, those who were voluntarily motivated
to undergo follow-up brain MRI at least 1 year after the
initial brain MRI were considered as candidates for inclu-
sion in this study. The timing was arbitrary, and the follow-
up MRI deadline was set as December 2021. The inclusion
criteria were as follows: age ≥ 20 years at baseline assess-
ment, no impairment in instrumental functions of daily
living, ability to visit our center independently for a current
brain health examination, and provision of written informed
consent. The exclusion criteria were a history of neurolo-
gical disease (including stroke and dementia) or brain
injury, inability to undergo brain MRI, no MRI performed
at least 1 year after baseline assessment, incomplete data for
risk factors at baseline, or incomplete MRI for measurement
for total SVD score. Also excluded were subjects with a
baseline total SVD score of the full four points, as described
below in the “Determining the total SVD score and clas-
sification for analyses” section.
Standard protocol approvals, registrations, and
consent
All protocols were approved by the institutional review
boards at the Saga University Faculty of Medicine (approval
No. R3-21) and Kansai Medical University (approval No.
2021343). Written informed consent was obtained from all
subjects.
Baseline assessment
All subjects were examined by a general physician or a cer-
tified neurosurgeon. We recorded clinical characteristics such
as age, sex, smoking status, history of ischemic heart disease,
duration of education, actual blood pressure (BP) (systolic
BP, diastolic BP, pulse pressure, mean arterial pressure =
[systolic BP – diastolic BP]/3 + diastolic BP), presence of
hypertension, diabetes mellitus, dyslipidemia, and impaired
renal function (low estimated glomerular filtration rate
[eGFR] or proteinuria). Actual systolic and diastolic BP were
measured in the morning using a standard mercury sphyg-
momanometer, with the patient in the sitting position. The
definitions of hypertension, diabetes mellitus, and dyslipide-
mia were as described in detail in our previous report [12].
Significant proteinuria was defined as 1 + (30 mg/dL) or
more. Subjects who were smokers at the time of enrollment
were classified as current smokers. History of ischemic heart
disease and neurological disease, and duration of education
were obtained from each subject. General cognitive function
was assessed using the Mini Mental State Examination
(MMSE) [13], administered by a skilled nurse or physician (in
93% and 7% of subjects, respectively). A total MMSE score
< 27 was defined as impaired cognitive function [14, 15].
Brain MRI acquisition
Brain MRI was obtained using a 1.5 T scanner (EX-
CELART Vantage, version 7.0; Canon Medical Systems,
Tochigi, Japan). The imaging parameters (axial T1- and T2-
weighted imaging, fluid-attenuated inversion recovery, and
gradient-echo T2*-weighted sequences) are provided in the
supplementary materials (please see Supplementary
Method). Initial and follow-up brain MRI were performed
with the same equipment and parameters.
Determining the total SVD score and classification
for analyses
Components of the total SVD score, including lacunes,
CMBs, WMH, and PVS on basal ganglia (BG-PVS), were
classified according to the international consensus defini-
tions of standard criteria for reporting vascular changes on
neuroimaging [3].
According to the validated scoring system [6, 12], total
SVD scores were assigned as follows: presence of lacunes
or CMBs was defined as the presence of one or more foci (1
point each if present); presence of moderate to severe WMH
or periventricular hyperintensity (PVH) was defined as
either (early) confluent deep WMH (Fazekas score 2 or 3)
and/or irregular PVH extending into deep white matter
(Fazekas score 3) (1 point if present); and presence of
moderate to severe BG-PVS (i.e., ≥11 BG-PVS on one side)
(1 point if present). Thus, total SVD score ranged from 0 to
4. Progression of SVD was defined as an increase in total
SVD score of ≥ 1 point between baseline and follow-up
MRI. Therefore, subjects with a baseline total SVD score of
the full four points were excluded from the present study
because their score did not worsen any further.
Each finding at baseline was evaluated by two raters, as
described elsewhere [9, 16]. All findings on follow-up brain
MRI were evaluated by a single certified stroke neurologist
(T.I.) using the same criteria as above. All raters of SVD
findings on MRI were blinded to the clinical data. Inter-rater
reliability was calculated for each SVD finding (0 or 1
point) in 100 randomly selected scans and expressed as
Cohen’s κ (i.e., all raters of the initial MRI vs. a single rater
of the follow-up MRI). Intra-rater reliability for the MRI
findings was calculated in 100 randomly selected scans that

were scored twice at an interval of ≥ 8 weeks, with raters
blinded to the initial rating, expressed as Cohen’s κ. The
details of the evaluation criteria and the results of inter- and
intra-rater reliability are provided in the supplementary
materials (please see Supplementary Table I). Briefly, inter-
rater reliability was within the range of 0.71–0.91 and intra-
rater reliability was within the range of 0.79–0.94.
Statistical analyses
We compared four groups in the baseline analysis, categorized
by total SVD scores of 0, 1, 2, and 3. The demographic and
clinical findings are presented as means (standard deviation
[SD]), medians (interquartile range), or frequencies (percen-
tages). For the group comparisons, the χ2 test, Fisher’s exact
test, t test, Wilcoxon rank sum test, one-way analysis of var-
iance (ANOVA), or Kruskal–Wallis test was applied, as
appropriate. Regarding the primary analysis, univariate and
multivariate logistic regression analyses were performed to
identify the relationship between worsening total SVD score
and the clinical findings. Age, sex, hypertension, and diabetes
mellitus at baseline were considered a priori as potential
confounders of total SVD score because of their strong asso-
ciation with sporadic SVD [1]. As aging (i.e., passage of time)
is also considered to be related to progression of SVD, the
time elapsed between baseline and follow-up MRI imaging
examinations (follow-up duration) was also included as a
potential confounder. Actual measured BP was adjusted only
for age, sex, diabetes mellitus, and follow-up duration. Simi-
larly, in the secondary analysis, we explored risk factors
leading to a follow-up total SVD score of ≥ 2 in subjects with a
baseline total SVD score of 0 or 1. In sensitivity analysis,
primary and secondary analyses were performed only for
subjects in middle age (age 40–65 years) at baseline. Statistical
significance was set at p < 0.05 for all tests. All statistical
analyses were conducted using JMP 16.1.0 statistical software
(SAS Institute Inc, Cary, NC, USA).
Results
Figure 1 shows a flow diagram of subject selection. Of 1729
potential subjects who underwent the health screening test,
32 were initially ineligible for analysis due to refusal to
consent, history of neurological disease or brain injury, or
inability to obtain MRI. Among the 1,697 eligible subjects,
1,023 were excluded due to incomplete data. After
excluding a further 9 with a baseline total SVD score of
the full 4 points, a final total of 665 subjects (mean age,
57.7 years and age range, 30–84 years at baseline; mean
age, 64.7 years at follow-up; 48.7% male) were included in
this study. Median time from baseline to follow-up MRI
was 7.3 years (interquartile range, 4.1–10.0 years).
T. Ide et al.
Comparison of the baseline clinical characteristics between
the included and excluded subjects (Supplementary Table
II) revealed no significant differences.
Table 1 shows the clinical characteristics at baseline in
the overall subjects and in each of the total SVD score
groups (scores 0–3). Those with a total SVD score of 0
accounted for 69.8%, and the remaining (30.2%) scored ≥ 1
point. In ANOVA, there were significant differences in
variables or prevalence among the groups for all variables
except sex, current smoking, dyslipidemia, and follow-up
duration. In summary, conventional vascular risk factors
and renal dysfunction, as well as low education and MMSE,
were most common in subjects with the highest total SVD
scores.
Figure 2 shows the numbers of subjects with combined
total SVD scores at baseline MRI (0–3) and the same
subjects’ scores at follow-up MRI (0–4) in a 4 × 5 cross-
classification. SVD worsened in 154 (23.2%), showed no
change in 453 (68.1%), and improved in 58 (8.7%). Sub-
jects with the highest total SVD score (i.e., score 3) at
baseline showed the greatest subsequent increase in score;
whereas SVD worsened in 22.0%, 23.5%, 25.6%, and
53.8% of subjects who scored 0, 1, 2, and 3, respectively, at
baseline.
Table 2 shows the results of univariate and multivariate
logistic regression analyses of the risk factors associated with
the progression of SVD. In multivariate analyses, the pro-
gression of SVD was associated with age (per 10-year
increase); presence of hypertension; systolic BP (per SD
increase), diastolic BP (per SD increase), mean arterial pres-
sure (per SD increase) and follow-up duration (per year).
The results of the secondary and sensitivity analyses are
listed in Supplementary Tables III, IV and V. In brief, the
secondary analysis revealed that a subsequent follow-up
total SVD score of ≥ 2 points in subjects who had a baseline
total SVD score of 0 or 1 was associated with age, current
smoking, diastolic BP, mean arterial pressure, and follow-
up duration. The sensitivity analysis was performed in 527
middle-aged subjects (79.2% of the total). Regarding the
sensitivity analysis of the primary analysis, the factors
associated with worsening total SVD score in these subjects
included age, hypertension, systolic BP, diastolic BP, mean
arterial pressure, and follow-up duration. The sensitivity
analysis of the secondary analysis in middle-aged subjects
revealed age, current smoking, and follow-up duration as
the factors associated with a subsequent follow-up total
SVD score of ≥2 points.
Discussion
The main finding of this longitudinal study is that SVD
worsened in one in five (23.2%) neurologically healthy
Associations for progression of cerebral small vessel disease burden in healthy adults: the Kashima. . .

Total subjects who underwent

health screening
n = 1,729
Excluded n = 32
Refused consent n = 21
History of neurological disease or brain injury n = 10
Could not undergo MRI because of claustrophobia n = 1
Subjects eligible for analysis
n = 1,697

Excluded due to incomplete data n = 1,023

No MRI performed at least 1 year after baseline n = 978
Incomplete data for risk factors n = 29
Incomplete MRI for measurement for total SVD score n = 16

Baseline total SVD score of the full 4 points n = 9

Subjects included in analyses

n = 665

Fig. 1 Flow diagram of subject selection. MRI Magnetic resonance imaging, SVD Small vessel disease

Table 1 Demographic and clinical findings at baseline in all subjects and according to total SVD score with univariate comparison
All (n = 665) Score 0 Score 1 Score 2 Score 3 p-value
(n = 464, 69.8%) (n = 149, 22.4%) (n = 39, 5.9%) (n = 13, 2.0%)

Age, mean (SD), years 57.7 (8.8) 56.3 (8.5) 59.7 (8.6) 63.9 (6.6) 66.3 (7.3) < 0.001
Sex, male, n (%) 324 (48.7) 217 (46.8) 81 (54.4) 17 (43.6) 9 (69.2) 0.157
Current smoker, n (%) 117 (17.7) 79 (17.1) 30 (20.3) 5 (12.8) 3 (23.1) 0.644
Ischemic heart disease, n (%) 15 (2.3) 7 (1.5) 3 (2.0) 4 (10.3) 1 (7.7) 0.003
Hypertension, n (%) 244 (36.9) 141 (30.6) 70 (47.3) 23 (59.0) 10 (76.9) < 0.001
Systolic BP, mean (SD), mmHg 125.1 (17.1) 123.0 (16.2) 127.8 (17.8) 134.4 (19.2) 140.3 (16.3) < 0.001
Diastolic BP, mean (SD), mmHg 77.3 (11.3) 76.3 (10.6) 79.3 (13.0) 80.4 (10.5) 81.1 (12.0) 0.006
Pulse pressure, mean (SD), 47.8 (12.1) 46.7 (11.3) 48.5 (12.5) 53.9 (15.2) 59.2 (15.0) < 0.001
mmHg
Mean arterial pressure, mean 93.2 (12.3) 91.9 (11.6) 95.4 (13.5) 98.4 (12.0) 100.8 (11.6) < 0.001
(SD), mmHg
Diabetes mellitus, n (%) 60 (9.1) 31 (6.7) 18 (12.2) 10 (26.3) 1 (7.7) < 0.001
Dyslipidemia, n (%) 375 (56.9) 252 (54.7) 92 (62.6) 23 (60.5) 8 (61.5) 0.363
eGFR < 60 mL/min/1.73 m2, n (%) 54 (8.6) 32 (7.3) 16 (11.2) 2 (5.4) 4 (36.4) 0.004
Proteinuria, n (%) 25 (4.0) 12 (2.8) 6 (4.3) 3 (8.3) 4 (33.3) < 0.001
Education, median (IQR), years 12 (12–14) 12 (12–14) 12 (12–14) 12 (9–14) 12 (9–12) 0.008
MMSE score < 27, n (%) 36 (5.9) 18 (4.2) 12 (9.2) 4 (11.1) 2 (16.7) 0.027
Follow-up duration, median 7.3 (4.1–10.0) 7.2 (4.1–9.9) 8.0 (4.5–10.1) 6.5 (3.0–9.6) 7.9 (5.5–9.8) 0.164
(IQR), years
Data are presented as the mean (standard deviation) or median (interquartile range) for continuous variables and as the number (percentages) for
categorical variables
SVD Small vessel disease, BP Blood pressure, eGFR Estimated glomerular filtration ratio, MMSE Mini Mental State Examination, SD Standard
deviation, IQR Interquartile range
Less than 10% of all data were missing
 T. Ide et al.

Total SVD score at follow-up

0 1 2 3 4
362 83 14 4 1
Total SVD score at baseline
0
(78.0%) (18.0%) (3.0%) (0.9%) (0.2%)

43 71 28 6 1
1
(28.9%) (47.7%) (18.8%) (4.0%) (0.7%)

5 8 16 9 1
2
(12.8%) (20.5%) (41.0%) (23.1%) (2.6%)
1 0 1 4 7
3
(7.7%) (0%) (7.7%) (30.8%) (53.8%)
Fig. 2 Changes in total SVD scores between baseline MRI and follow- baseline and follow-up; boxes shaded gray: worsened total SVD score
up MRI. Boxes show the number of subjects (percentage) for each ( ≥ 1) at follow-up; boxes with dots: improved total SVD score at
combination of baseline and follow-up total SVD scores. White boxes follow-up. SVD, small vessel disease
with heavy black borders: no change in total SVD score between

Table 2 Logistic regression

Crude OR (95%CI) p-value Adjusted OR p-value
analyses of demographic and
(95%CI)
clinical findings relevant to total
SVD score worsening Age (per 10 years) 2.03 (1.60–2.56) < 0.001 2.08 (1.62–2.67)a < 0.001
Sex, male 1.18 (0.82–1.70) 0.361 1.26 (0.86–1.87)b 0.237
c
Current smoker 1.23 (0.78–1.95) 0.368 1.54 (0.90–2.63) 0.118
Ischemic heart disease 1.20 (0.38–3.83) 0.753 0.80 (0.24–2.72)c 0.725
Hypertension 1.97 (1.36–2.84) < 0.001 1.55 (1.05–2.29)d 0.027
Systolic BP (per SD = 17.1 mmHg) 1.44 (1.20–1.72) < 0.001 1.27 (1.04–1.54)d 0.018
Diastolic BP (per SD = 11.3 mmHg) 1.20 (1.01–1.44) 0.043 1.23 (1.01–1.50) d
0.037
Pulse pressure (per SD = 12.1 mmHg) 1.39 (1.16–1.66) < 0.001 1.15 (0.95–1.39)d 0.162
Mean arterial pressure (per 1.33 (1.11–1.60) 0.002 1.27 (1.04–1.55)d 0.017
SD = 12.3 mmHg
Diabetes mellitus 1.33 (0.74–2.41) 0.346 1.06 (0.57–1.99)e 0.852
Dyslipidemia 1.05 (0.73–1.51) 0.799 0.96 (0.65–1.41)c 0.843
eGFR <60 mL/min/1.73 m2 1.28 (0.68–2.39) 0.447 0.81 (0.41–1.59)c 0.547
Proteinuria 0.60 (0.20–1.76) 0.349 0.37 (0.12–1.16)c 0.089
c
Education (per year) 0.88 (0.81–0.95) 0.002 0.96 (0.87–1.05) 0.355
MMSE score < 27 0.81 (0.35–1.88) 0.618 0.56 (0.23–1.37)c 0.207
Follow-up duration (per year) 1.08 (1.06–1.11) < 0.001 1.10 (1.04–1.17)f 0.002
a b
Adjusted for sex, hypertension, diabetes mellitus, and follow-up duration, Adjusted for age, hypertension,
diabetes mellitus, and follow-up duration, cAdjusted for age, sex, hypertension, diabetes mellitus, and
follow-up duration, dAdjusted for age, sex, diabetes mellitus, and follow-up duration, eAdjusted for age, sex,
hypertension, and follow-up duration, fAdjusted for age, sex, hypertension, and diabetes mellitus
SVD Small vessel disease, BP Blood pressure, eGFR Estimated glomerular filtration ratio, MMSE Mini
Mental State Examination, SD Standard deviation, OR Odds ratio, CI Confidence interval

adults (mainly in midlife; median age, 57.7 years), and that In this study, the presence of hypertension and higher BP
age and hypertension at baseline, as well as subsequent values were associated with progression of SVD. SVD is
aging (i.e., follow-up duration), were related to progression classified into type 1 pathology (atherosclerosis [age and
of SVD burden. hypertension-related]), type 2 pathology (cerebral amyloid
Associations for progression of cerebral small vessel disease burden in healthy adults: the Kashima. . .
angiopathy), and others (types 3–6) [1]. Although patho-
logical data were not available for our cohort, the principal
finding that vascular risk factors (i.e., age, hypertension, and
high BP) were associated with the progression of SVD adds
a validated evidence that total SVD score is a favorable
indicator of “type 1 class” SVD.
Among vascular risk factors, hypertension and high BP
values had robust associations with progression of SVD.
Interestingly, among the BP components, systolic BP, dia-
stolic BP, and mean arterial pressure were associated with
the progression of SVD, whereas pulse pressure was not.
Among previous studies that have investigated the rela-
tionship between SVD biomarkers and BP components,
some have examined each BP component in a standardized
manner, and reported that the presence of CMBs was
associated with systolic BP, diastolic BP, and mean arterial
pressure [17], and that total SVD score was associated with
systolic BP and mean arterial pressure [12].
In the secondary analysis, current smoking status at base-
line was associated with a follow-up total SVD score of ≥ 2
points in subjects who had baseline total SVD scores of 0 or 1.
This finding implies that smoking cessation is an important
risk factor in addition to BP management in the mild stage of
SVD burden. A study of individual markers of SVD has
reported that current smoking was associated with CMBs and
that the combination of hypertension and current smoking had
a synergistic additive effect on the presence of CMBs [18]. A
similar effect was found for moderate to high total SVD scores
[6, 19]. Smoking may cause endothelial dysfunction and
vasodilation impairment due to decreased activity of endo-
thelial nitric oxide synthase and decreased level of nitric oxide
[20], and it has been reported that smoking and hypertension
have additive effects on endothelial dysfunction and vascular
injury [21, 22]. To develop an effective prevention strategy for
stroke and dementia caused by SVD, it is necessary to deter-
mine whether the combination of vascular risk factors such as
hypertension and smoking has a synergistic additive effect on
the progression of SVD.
In the sensitivity analysis, selected only for middle-aged
subjects (aged 40–65 years), the results were consistent with
those in the primary analysis. Because the level of cardio-
vascular health after mid-life, as indicated by Life’s Simple
7 score, is associated with the development of stroke and
dementia [23, 24], it is crucial to assess brain health in
middle age (through total SVD score) and conduct inter-
ventions for lifestyle diseases as prevention against future
stroke and dementia.
Brain and kidney microvasculatures share anatomic and
functional vasoregulatory similarities, and it is thought that
among the various cerebrovascular diseases, SVD is prob-
ably most strongly associated with impaired renal function
[25]. Nonetheless, we were unable to demonstrate an
association between renal dysfunction and progression of
SVD. The present study was based on a neurologically
healthy cohort, which potentially influenced the results.
Interestingly, 8.7% of subjects had an improved total
SVD score at follow-up. To date, little is known about
longitudinal improvement of the total SVD score, although
some previous studies have reported improvement in sev-
eral neuroimaging markers of SVD. Some CMBs seemed to
disappear over time in 5.9% of those with CMB at baseline
[26]. Another study reported that white matter changes
generally progress over time and do not show improvement
[27]. In contrast, a slight improvement of white matter
changes has been reported with atorvastatin [28]. Our
additional analysis revealed no significant differences in
clinical characteristics between those subjects in whom total
SVD score improved and those in whom there was no
change (data not shown). As the improvement in total SVD
score could be influenced by differences among raters, as
well as subtle differences in imaging slices, we were unable
to determine the mechanism of dynamic improvement
of SVD.
The strengths of our study include its prospective design,
the large number of neurologically healthy subjects with long-
term imaging follow-up, standardized images obtained with
identical baseline and follow-up conditions using the same
equipment and parameters, and the high inter-rater reliability
of the two image assessments. Nevertheless, there are several
limitations in the present study. First, selection bias should be
considered. Subjects in our study underwent brain health
examinations at their own expense, potentially selecting for a
subpopulation that is relatively affluent with an interest in their
own health; it is known that socioeconomic status is an
important factor in cardiovascular disease [29]. Second,
although our baseline cohort included more than 1,600 sub-
jects, 1,032 were excluded from the final analyses, presumably
because no follow-up MRI examination had been scheduled.
Therefore, of these two limitations, the first (selection bias)
might be more accentuated. However, in a comparison of the
background characteristics of the subjects excluded from and
included in the final analyses, the two groups were found to be
generally identical (please see Supplementary Table II). Third,
the timing of follow-up MRI was dependent on the subject.
Therefore, we could not perform the Cox proportional hazards
regression model or Kaplan–Meier method, which are usually
applied in longitudinal studies. To minimize the influence of
this issue, we included follow-up duration as a confounding
factor in the multivariate analysis. Fourth, we could not
ascertain the type and severity of SVD pathologically.
Perspective of Asia
SVD with type 1 pathology [age-related or vascular risk
factor-related] has been reported to be more common in

Asian population than in Western population [30]. Given
that intracerebral hemorrhage (especially hypertensive one
[i.e. type 1 SVD]), a representative disease of vascular
dysfunction due to microvascular atherosclerosis, the inci-
dence is 2 or 2.5-fold higher in Asian compared to Western
[31, 32], preventive strategies for the progression of SVD
are more important in the Asian population.
Conclusion
Our observational longitudinal cohort study adds novel
evidence of associations with the progression of SVD bur-
den in neurologically healthy adults. The present finding
that management of mid-life hypertension might be the
most important target for preventing sporadic global SVD
progression in old age could be crucial for initiating a future
prospective interventional study to test this relationship. In
addition, it is a further challenge to investigate how sus-
tained blood pressure status affects the progression of SVD.
Funding This study was supported by a Grant-in-Aid for Scientific
Research (C), JSPS KAKENHI (Grant No. 21K10510).
Compliance with ethical standards
Conflict of interest The following conflict of interest is outside the
submitted work. Yakushiji reports personal fees from Daiichi-Sankyo.
The other authors report no conflicts of interest.
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