Hypertension and white matter lesions are
independently associated with apathetic behavior in
healthy elderly subjects: the Sefuri brain MRI study
Hiroshi Yao1, Yuki Takashima1, Takahiro Mori1, Akira Uchino2, Manabu Hashimoto1, Takefumi Yuzuriha1,
Yoshikazu Miwa3and Toshiyuki Sasaguri3
Apathy is defined as a syndrome of primary loss of motivation not attributable to emotional distress, intellectual impairment
or consciousness disturbance. The aim of our study was to investigate the effects of vascular risk factors and silent ischemic
brain lesions on apathetic behavior of community-dwelling elderly subjects. Brain MRI and other medical examinations were
performed on 222 non-demented community-dwelling elderly subjects (96 men and 126 women, average age 70.1 years). The
apathy group was defined as the most apathetic quintile determined by Starkstein’s apathy scale. Silent infarction, deep white
matter lesions (DWMLs) and periventricular hyperintensities were detected in 12.2, 39.2 and 22.5%, respectively. Linear
regression analysis (Pearson) revealed that the scores on the apathy scale correlated slightly but significantly with logarithmically
transformed scores of the Modified Stroop Test (r¼0.135, P¼0.045), but not with the Mini-Mental State Examination. The
apathy group tended to have more high blood pressure (141.6/82.6 vs. 136.1/79.6mmHg), less prevalent hyperlipidemia
(18 vs. 35%) and lower serum albumin. Multivariate analysis (the forward stepwise method of logistic analysis) revealed an
independent correlation between the apathy and grade of DWMLs (odds ratio 1.826, 95% confidence interval (CI) 1.129–2.953
per grade) or diastolic blood pressure (DBP) (odds ratio 1.055, 95% CI 1.014–1.098 per mmHg) after adjusting for possible
confounders. The mean apathy scale score in the DBP^90mmHg group was significantly lower (more apathetic) than that in
the DBPo80 group (P¼0.011, analysis of covariance). This study showed that hypertension and DWMLs are independently
associated with apathy in healthy elderly subjects.
Hypertension Research (2009) 32, 586–590; doi:10.1038/hr.2009.65; published online 8 May 2009
Keywords: asymptomatic stroke; blood pressure; lacunar infarction; magnetic resonance imaging; depression
Hypertension is one of the major risk factors for vascular dementia or
vascular cognitive impairment. The Hisayama Study showed that age,
prior stroke episodes, systolic blood pressure and alcohol consump-
tion were independent risk factors for vascular dementia.1Although
the HYVET trial of lowering blood pressure in subjects aged 80 years
or older was stopped early because of a substantial reduction in total
mortality and stroke by the treatment, the meta-analysis of HYVET
and three similar trials might support antihypertensive treatment to
reduce the risk of incident dementia.2Epidemiological and clinical
studies have established an association between cardiovascular disease
and neuropsychiatric symptoms such as depression and apathy. In a
population-based sample of incident Alzheimer’s disease, an explora-
tory analysis showed that vascular factors such as hypertension and a
history of stroke were associated with various neuropsychiatric symp-
toms, including apathy.3Apathy is defined as a syndrome of primary
loss of motivation not attributable to emotional distress, intellectual
impairment or consciousness disturbance.4,5Apathy is one of the most
common neuropsychiatric symptoms present in 3.2% of the general
population, 14.7% of subjects with mild cognitive impairment and
35.9% of subjects with dementia.6
Multiple lacunes and leukoaraiosis cause various neuropsychiatric
symptoms7–10as well as cognitive impairment.11–13According to the
vascular depression hypothesis, small vessel diseases such as silent brain
infarction (that is, subcortical lacunes) and/or white matter lesions
(WMLs) may disrupt frontal–subcortical circuits and generate depres-
sive symptoms.7Apathy can be the clinical expression of a depressed
state, but it is distinct from depression as a disorder of motivation
rather than mood. The working group of Vascular Cognitive Impair-
ment Harmonization Standards has recommended that measure of
apathy would be important to include, detecting and quantifying
apathetic personality changes, which are rather common early mani-
Received 22 January 2009; revised 27 March 2009; accepted 2 April 2009; published online 8 May 2009
1Center for Emotional and Behavioral Disorders, National Hospital Organization Hizen Psychiatric Center, Saga, Japan;2Department of Radiology, Saitama Medical University
International Medical Center, Saitama, Japan and3Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence: Dr H Yao, Center for Emotional and Behavioral Disorders, Hizen Psychiatric Center, Mitsu 160, Yoshinogari, Kanzaki, Saga 842-0192, Japan.
Hypertension Research (2009) 32, 586–590
& 2009 The Japanese Society of Hypertension All rights reserved 0916-9636/09 $32.00
festations of subcortical vascular disease.13However, no study so far
has investigated the effects of ‘silent’ subcortical vascular lesions on
apathetic behavior of healthy elderly subjects. Therefore, we examined
the effects of vascular risk factors and silent ischemic brain lesions on
an apathetic mental condition in community-dwelling people.
Since 1997, we randomly contacted approximately 1200 inhabitants aged 40 years
or older, living in the rural community of Sefuri village, Saga, Japan, through the
village office, and completed a brain MRI study in 720 subjects. Between 2003
and 2007, 222 elderly subjects aged 60 years or older were examined using the
Starkstein’s apathy scale.4These subjects were living independently at home
without apparent dementia. Anyone with symptomatic cerebrovascular diseases,
brain tumor, malignant neoplasm and psychiatric disorders, including depression
or a history of head trauma, was excluded. We did not experience participants
with Parkinson’s disease. The local ethics committee approved this study, and
written informed consent was obtained from all participants.
Definition of vascular risk factors
Participants underwent a structured clinical interview, a neurological examina-
tion, general hematology tests, biochemistry tests and electrocardiograms.
Blood pressure was measured in the sitting position by the standard cuff
method after 5min of rest. Vascular risk factors were defined as described
earlier.14Briefly, arterial hypertension was considered present if a subject had a
history of repeated blood pressure recordings above 140/90mmHg or the
subject was being treated for hypertension. Diabetes mellitus was defined as
fasting plasma glucose greater than 7.77mmoll?1and/or HbA1c greater than
6.0%, or an earlier diagnosis of diabetes mellitus. Hyperlipidemia was defined
as total serum cholesterol concentration greater than 5.69mmoll?1or if the
subject was being treated for hyperlipidemia.
Assessment of apathy and cognitive function
All subjects underwent the Mini-Mental State Examination as the standard
screening test and Modified Stroop Test as a screen for frontal lobe impair-
ment.15Depressive mood and insomnia was defined as ‘always’ or ‘frequent’
(more than sometimes) presence of these symptoms filled in a structured
questionnaire. The terms of the Starkstein’s scale4were translated into Japa-
nese,16and we (internal medicine (HY), psychiatry (TY) and neurology (YT))
further discussed and corrected the minor details of language. Each item on the
apathy scale was quantified on a visual analog scale in which one end of a
60-mm-long line is ‘absolutely correct’ and the other end is ‘completely
wrong’ (Figure 1). Of the 14 questions on the apathy scale, item-total
correlations of question nos. 3 and 11 were weak (r¼0.45 and 0.46, respec-
tively); other questions showed better correlation (r¼0.55–0.72) with total
score. Therefore, we excluded the scores of these two questions from the
analysis. The subject was judged as having apathy if the total score was below
the fifth quintile.
Assessment of MRI findings
The combination of T1WI, T2WI and fluid-attenuated inversion recovery
(FLAIR) images is required to accurately detect both silent brain infarction and
mild WMLs.17,18Therefore, T1-weighted (TR/TE¼510/12ms), T2-weighted
(TR/TE¼4300/110ms)and FLAIR (TR/TI/TE¼6750/1600/22ms) images were
obtained with a slice thickness of 6mm, with a 1-mm interslice gap with a brain
MRI (1.0T; Shimadzu, Magnex XP, Kyoto, Japan). Brain infarcts were shown as
low signal intensities on T1-weighted images, and their size was 5mm or larger
(Figure 2). The WMLs were defined as isointense with normal brain parench-
yma on T1-weighted images and as high signal intensity areas on T2-weighted
images. We used the validated rating scale of deep WMLs (DWMLs) by Fazekas
et al.18: Grade 0, absent; Grade 1, punctate foci; Grade 2, beginning confluence
of foci; and Grade 3, large confluent areas. For periventricular hyperintensities,
we determined the presence and severity (Grade 0, absent; Grade 1, pencil
thin; Grade 2, smooth halo lining) using FLAIR images. All scans were
reviewed independently by two authors (HY and AU) who were blinded to
all clinical data. In the case of disagreement between the raters, a consensus
reading was held.
All values were given as mean±s.d. except for error bars in Figures 1 and 3. We
used an SPSS software package (version 11; Chicago, IL, USA) for the statistical
analysis. Normality of the distribution was tested with the Shapiro–Wilk
statistics. For the univariate analysis, the t-test for continuous variables, the
w2-test for categorical variables and the non-parametric Mann–Whitney u-test
for variables with skewed distribution were used as appropriate. We chose the
variables for entry into the multivariate analysis on the basis of the clinical and
neuroradiological findings with P-values of o0.20 after univariate testing.
Multivariate analysis was performed using the forward stepwise method of
logistic analysis. The mean apathy scale score, adjusted for age, and grades of
DWMLs were compared among the three blood pressure categories with
analysis of covariance.
14. Would you consider yourself apathetic?
13. Are you neither happy nor sad, just in between?
12. Do you need a push to get started on things?
11. Are you unconcerned with many things?
10. Are you indifferent to things?
9. Does someone have to tell you what to do each day?
8. Do you have the energy for daily activities?
7. Do you have motivation?
6. Do you have plans and goals for the future?
5. Are you always looking for something to do?
4. Do you put much effort into things?
3. Are you concerned about your condition?
2. Does anything interest you?
1. Are you interested in learning new things?
Apathy (+)Apathy (-)
Mean ± S.E.M.
Figure 1 Starkstein’s apathy scale and itemized scores of the groups divided by the lowest quintile of total scores. Each item on Starkstein’s apathy scale4
was quantified on a visual analog scale in which one end of a 60-mm-long line is ‘absolutely correct’ and the other end is ‘completely wrong.’ Participants
marked where it is appropriate for each question, and then the distance was measured and counted as a score. In this study, we used the original
arrangement in which the directions of the apathetic state were changed between question nos. 8 and 9, but this figure shows the left side as apathetic. The
scores range from 0 to 720; lower scores indicate more severe apathy.
Hypertension, leukoaraiosis and apathy
H Yao et al
The subjects comprised 96 men and 126 women with a mean age of
70.1 years and a mean educational level of 10.2 years. Hypertension
was present in 108 subjects. Blood pressure levels were 128.7±14.4/
78.2±7.7, 144.2±15.1/80.8±10.2 and 163.3±8.1/94.7±4.7mmHg
in normotensive subjects (n¼114), treated hypertensive subjects
(n¼97) and non-treated hypertensive subjects (n¼11), respectively.
The prevalence of diabetes mellitus, hyperlipidemia and heart disease
were 14.0, 32.0 and 4.5%, respectively. Silent brain infarction was
detected by MRI in 26 subjects of 222 participants (12.2%). All except
one infarction were small and deeply situated lacunar infarcts.
DWMLs and periventricular hyperintensities were present in 87
(39.2%) and 50 (22.5%) subjects, respectively. Of the 87 subjects
with DWMLs, small punctate (grade 1, n¼62) lesions were the most
prevalent followed by early confluent (grade 2, n¼24) and large
confluent (grade 3, n¼1). DWMLs were more prevalent in the apathy
group (55 vs. 35%) (Table 1).
The apathy scale appeared to have an almost normal distribution,
but the Shapiro–Wilk test did not significantly support the normality
(P¼0.039) (Figure 4). The apathy group, defined as the most apathetic
quintile determined by the apathy scale, tended to have more high
blood pressure (141.6/82.6 vs. 136.1/79.6mmHg), less prevalent
hyperlipidemia (18 vs. 35%) and lower serum albumin (41.5±3.5
vs. 43.1±3.4gl?1) (Table 1). Although the differences of Modified
Stroop Test between the groups with or without apathy did not reach a
statistical significance (P¼0.093, Mann–Whitney u-test), linear regres-
sion analysis revealed that the apathy scale score correlated signifi-
cantly with the logaristic-transformed score of Modified Stroop Test
(r¼0.135, P¼0.045), but not with Mini-Mental State Examination.
The prevalence of depressive mood and insomnia was not significantly
different between the groups. When possible confounders were
entered into the multivariate logistic regression model (the forward
stepwise method), the independent predictors of apathy were diastolic
blood pressure (DBP) (odds ratio (OR) 1.055; 95% confidence
interval (CI) 1.014–1.098 per 1mmHg), hyperlipidemia (OR 0.371;
95% CI 0.153–0.901), albumin (OR 0.317; 95% CI 0.115–
0.870g?1l?1) and DWMLs (OR 1.826; 95% CI 1.129–2.953 per
grade) (Table 2). The mean apathy scale score in the DBP^90mmHg
group was 439 (95% CI 402–477), which was significantly lower than
Silent Brain Infarction PVHs
Deep White Matter Lesions
C, grade 1, punctate ( ); D, grade 2, becoming confluent (); E, grade 3, large confluent
Figure 2 MRI of silent brain infarction (a), periventricular hyperintensities (PVHs) (b) and deep white matter lesions (c–e).
Figure 3 Apathy scale according to blood pressure category. Graph shows
mean values and 95% confidence interval of apathy scale adjusted for age
and the grade of deep white matter lesions. *P¼0.011 vs. diastolic blood
pressure (DBP) o80mmHg.
Hypertension, leukoaraiosis and apathy
H Yao et al
497 (95% CI 474–521) in the DBPo80 group (P¼0.011, analysis of
covariance) (Figure 3).
This is the first study that showed that hypertension and DWMLs
might contribute to apathy syndrome in healthy elderly people. Apathy
was slightly but significantly associated with frontal lobe dysfunction
but not with global cognitive function assessed with Mini-Mental State
Examination. Apathetic subjects were not depressed in terms of the
similar prevalence of depressed mood and insomnia with non-apa-
thetic subjects. Subcortical vascular disease and DWMLs seen in
community-dwelling subjects are associated with cognitive impairment
or dementia, depression and gait disturbance.7–9,11–13,19Similarly,
multiple lacunes cause frontal lobe dysfunction,15including a difficulty
in shifting set, impaired executive functions, decreased verbal fluency
and apathy. Apathy observed in this study might have occurred when
the frontal cortex was functionally disconnected from relevant limbic
input through basal ganglia by DWMLs.20
Small-vessel disease is the predominant cause of silent brain
infarction and WMLs.19Apart from age, the main risk factors for
WMLs are vascular risk factors, particularly hypertension. In our
experience, although age was the major factor concerning both
DWMLs and periventricular hyperintensities, hypertension was also
but less robustly associated with WMLs (OR 1.6) compared with silent
brain infarction (OR 3.2) (unpublished observation, abstract appeared
in Stroke 2007; 38: 535). In the Perindopril Protection Against
Recurrent Stroke Study, the risk of new WMLs was reduced by 43%
in the active antihypertensive treatment group, with a reduced blood
pressure by 11.2/4.3mmHg compared with the placebo group.21
Although patients vulnerable to hypotension are probably not well
represented in earlier trials such as Perindopril Protection Against
Recurrent Stroke Study, the treatment of vascular risk factors is all that
physicians have at their disposal.19Furthermore, DBP related with
apathy independent of WMLs and silent infarction in this study.
Table 1 Characteristics of study population with or without apathy
Apathy (+)Apathy (?)
Body mass index (kgm?2)
Depressive mood (%)
Mini-Mental State Examination
Modified Stroop Test (s)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Diabetes mellitus (%)
Heart disease (%)
Alcohol (units per week)
Fasting blood glucose (mmoll?1)
Total cholesterol (mmoll?1)
HDL cholesterol (mmoll?1)
Uric acid (mmoll?1)
Silent brain infarction (%)
Deep white matter lesions (%)
Periventricular hyperintensities (%)
Abbreviation: NS, not significant.
Values are mean±s.d.
Table 2 Logistic regression analysis of factors predicting apathetic
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Total cholesterol (mmoll?1)
HDL cholesterol (mmoll?1)
Silent brain infarction (number)
Deep white matter lesions (grade)
Periventricular hyperintensities (grade)
0.026 0.317 0.115–0.870
0.014 1.826 1.129–2.953
Abbreviations: 95% CI, 95% confidence interval; OR, odds ratio.
Frequency Stem & Leaf
0 0 3 3
5 6 6 6 8 8 9 9
0 0 1 1 2 2 3 3 4 4 4 4 4 4 4 4
5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9
0 0 0 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 3 3 3 3 3 3 3 3 4 4 4 4
5 5 5 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 7 7 7 7 8 8 8 8 8 8 9 9 9 9 9 9 9 9
0 1 1 1 1 1 2 2 2 3 3 3 3 4 4 4 4 4 4 4 4 4 4
5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 8 8 8 9 9 9 9 9
0 0 0 0 0 1 1 1 1 2 2 3 4 4 4 4
5 5 5 5 5 5 7 7 7 8 8 8 9 9
0 0 1 1 2
Stem width :
Each leaf :
1 case (s)
Figure 4 Stem-and-leaf plot of apathy scale. The scores for apathy group defined as the most apathetic quintile are shown in bold.
Hypertension, leukoaraiosis and apathy
H Yao et al
Hypertension causes impaired cerebral microcirculation22or break-
down of the blood–brain barrier,23which may contribute to the
development of cognitive impairment. In chronic hypertension,
both the lower and upper limits of cerebral blood flow autoregulation
are shifted toward a higher blood pressure as a result of structural
alterations in small arteries.24Consequently, the hemodynamic reserve
in hypertensive individuals is reduced, which predisposes hyperten-
sives to circulatory insufficiency in the brain,25and possible brain
dysfunction including cognitive impairment and apathy. Taken
together, on the basis of facts on the treatable nature of hypertension
and WMLs, it should be emphasized that apathy associated with
hypertension and/or DWMLs in the general population is considered
to be potentially preventable.
The limitation of this study would be that the apathy group was
operationally defined by the self-rating apathy scale, and the clinical
diagnosis of apathy was not confirmed by using a psychiatric structured
interview. We asked five experienced psychiatrists how an assumed
‘average’ apathetic patient with moderate symptoms would score on
this apathy scale, and we found that the upper limit (that is, mean+2
s.d.) of the five scores was 320 (unpublished observation). In this study,
the mean score of the apathy group was 321±46 (s.d.). Therefore, we
could have detected a mild apathetic behavior in healthy elderly
subjects, using the apathy scale modified as an analog visual scale.
Although our exploratory analysis found that lower levels of serum
albumin and cholesterol were independently associated with apathy, the
cause–result relationship of this altered nutritional status and apathy is
not clear from the present cross-sectional analysis. Apathy might interfere
with eating behavior, resulting in the 1.6gl?1lower albumin and lower
prevalence of hyperlipidemia (18 vs. 35%). Low serum albumin levels are
observed in association with protein–energy malnutrition or non-thyr-
oidal illness syndrome commonly seen in various illnesses. However, the
albumin levels in our subjects were much higher than those in the cases
reported by Hama et al.26Alternatively, apathetic behavior-altered food
intake could contribute to the development of DWMLs as a consequence
of insufficient nutrients, such as decreased plasma tryptophan, which we
earlier suggested as one of the causative factors for DWMLs.27,28
However, these possibilities remain only speculative, and these associa-
tions may be of interest in a future study.
In conclusion, this study showed that DWMLs and high blood
pressure might contribute to apathy in healthy elderly subjects. This
apathetic tendency was not related to age, global cognition or depressive
symptoms. The intervention directed at hypertension and prevention of
silent ischemic brain lesions, particularly DWMLs, would be beneficial
to attenuate the motivation loss in healthy elderly subjects.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
We wish to express special thanks to T Muto and K Yamamoto for technical
assistance with the laboratory examinations and the MRI scanning, and to N
Kawahara-Ideno for registration of participants.
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Hypertension, leukoaraiosis and apathy
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