Differences in Brain Morphology between Hydrocephalus Ex Vacuo and Idiopathic Normal Pressure Hydrocephalus

Abstract

Objective:
The distinction between idiopathic normal pressure hydrocephalus (iNPH) and hydrocephalus ex vacuo caused by encephalic volume loss remains to be established. This study aims to investigate radiological parameters as clinically useful tools to discriminate iNPH from hydrocephalus ex vacuo caused by Alzheimer's disease (AD).

Methods:
A total of 54 patients with ventriculomegaly (iNPH, 25; hydrocephalus ex vacuo, 29) were recruited in this study. Consequently, nine radiological parameters were compared between iNPH and hydrocephalus ex vacuo using magnetic resonance imaging (MRI).

Results:
A small callosal angle (CA), the Sylvian fissure dilatation, and absence of narrowing of superior parietal sulci discriminated the iNPH group from the hydrocephalus ex vacuo group (p<0.05). The final binary logistic regression model included narrowing of superior parietal sulci, degrees of the CA, and height of the Sylvian fissure after controlling for age and global Clinical Dementia Rating (CDR). The composite score made from these three indicators (narrowing of superior parietal sulci, degrees of the CA, and height of the Sylvian fissure) was statistically different between iNPH and hydrocephalus ex vacuo.

Conclusion:
The narrowing of the CA, dilatation of the Sylvain fissure, and narrowing of superior parietal sulci may be used as radiological key indices and noninvasive tools for the differential diagnosis of iNPH from hydrocephalus ex vacuo.

Full text

Copyright
©
2021 Korean Neuropsychiatric Association 1
INTRODUCTION
Alzheimer’s disease (AD) which causes cognitive decline of-
ten demonstrates moderate to severe ventriculomegaly. is
pathology is called, known as hydrocephalus ex vacuo, a com-
Print ISSN 1738-3684 / On-line ISSN 1976-3026
OPEN ACCESS
pensatory enlargement of the cerebrospinal uid (CSF) spaces
caused by degenerative encephalic volume loss. Idiopathic nor-
mal pressure hydrocephalus (iNPH) typically manifests during
adult life as an insidiously progressive, chronic disorder that
lacks an identiable antecedent cause.1 It is characterized by
ORIGINAL ARTICLE
Dierences in Brain Morphology between Hydrocephalus
Ex Vacuo and Idiopathic Normal Pressure Hydrocephalus
Minkyung Kim1*, Sun-Won Park2,3*, Jun-Young Lee4 , Hongrae Kim4, Jung Hyo Rhim2, Soowon Park5,
Jee-Young Lee6, Hwancheol Son7, Yu Kyeong Kim8, and Sang Hyung Lee9 
1Seoul National University College of Medicine, Seoul, Republic of Korea
2Department of Radiology, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
3Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea
4Department of Psychiatry, Seoul National University College of Medicine & SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
5Department of Teacher Education, College of Liberal Arts and Interdisciplinary Studies, Kyonggi University, Suwon, Republic of Korea
6Department of Neurology, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
7Department of Urology, Seoul National University College of Medicine & SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
8Department of Nuclear Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
9Department of Neurosurgery, Seoul National University College of Medicine & SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
Objective e distinction between idiopathic normal pressure hydrocephalus (iNPH) and hydrocephalus ex vacuo caused by ence-
phalic volume loss remains to be established. is study aims to investigate radiological parameters as clinically useful tools to discrimi-
nate iNPH from hydrocephalus ex vacuo caused by Alzheimer’s disease (AD).
Methods A total of 54 patients with ventriculomegaly (iNPH, 25; hydrocephalus ex vacuo, 29) were recruited in this study. Consequent-
ly, nine radiological parameters were compared between iNPH and hydrocephalus ex vacuo using magnetic resonance imaging (MRI).
Results A small callosal angle (CA), the Sylvian ssure dilatation, and absence of narrowing of superior parietal sulci discriminated
the iNPH group from the hydrocephalus ex vacuo group (p<0.05). e nal binary logistic regression model included narrowing of su-
perior parietal sulci, degrees of the CA, and height of the Sylvian ssure aer controlling for age and global Clinical Dementia Rating
(CDR). e composite score made from these three indicators (narrowing of superior parietal sulci, degrees of the CA, and height of the
Sylvian ssure) was statistically dierent between iNPH and hydrocephalus ex vacuo.
Conclusion e narrowing of the CA, dilatation of the Sylvain ssure, and narrowing of superior parietal sulci may be used as radio-
logical key indices and noninvasive tools for the dierential diagnosis of iNPH from hydrocephalus ex vacuo.
Psychiatry Investig
Key Words Normal pressure hydrocephalus, Dementia, Hydrocephalus ex vacuo, Alzheimer’s disease, Magnetic resonance imaging.
Received: September 17, 2020 Revised: December 30, 2020 Accepted: April 10, 2021

Correspondence: Jun-Young Lee, MD, PhD
Department of Psychiatry, Seoul National University College of Medicine & SMG-SNU Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul 07061, Re-
public of Korea
Tel : +82-2-870-2581, Fax: +82-2-870-2587, E-mail: benji@snu.ac.kr

Correspondence: Sang Hyung Lee, MD, PhD
Department of Neurosurgery, Seoul National University College of Medicine & SMG-SNU Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul 07061,
Republic of Korea
Tel : +82-2-870-2302, Fax: +82-2-870-3864, E-mail: nslee@snu.ac.kr
*ese authors contributed equally to this work.
Portions of this paper were presented in poster form at the Alzheimer’s Association International Conference in Los Angeles, USA, on July 14–17, 2019.
cc is is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
https://doi.org/10.30773/pi.2020.0352
Psychiatry Investig 2021 July 16 [Epub ahead of print]

2 Psychiatry Investig
AD and iNPH
ventricular enlargement in the setting of normal intracranial
pressure with no visible obstruction to CSF ow. Additionally,
there can be other various imaging ndings such as enlarge-
ment of the temporal horns of the lateral ventricles, callosal an-
gle of 40 degree or more, evidence of altered brain water con-
tent, and an aqueductal or fourth ventricular ow void on MRI.
Clinically, gait and/or balance impairments are usual symptoms,
and ndings may also include disturbances in cognition and
control of urination. is condition represents an increasingly
signicant health issue due to steadily growing survival age of
the population within the developed countries.2
It oen presents cognitive impairment similar to AD, due
usually to a gradual block of the drainage of CSF in the brain.
e proper dierential diagnosis for iNPH holds clinical signif-
icance because shunt therapy can improve its clinical symptoms
unlike those of AD.3 Furthermore, a recent normal pressure hy-
drocephalus (NPH) study suggested that the presence of AD
pathology predicts poor prognosis aer shunt therapy, accen-
tuating the imperative clinical value for an accurate dierential
diagnosis between AD and iNPH.4 Although the CSF tap test
is an invasive procedure and lacks sensitivity (0.260.61) for di-
agnosing iNPH, it is eective in predicting shunt response for
patients with ventriculomegaly.5 erefore, researches have fo-
cused on improving diagnosis through noninvasive imaging
techniques between these two diseases. Since it is reported that
similar to AD, the prevalence of NPH increases with age,6 dis-
tinguishing noninvasively iNPH from hydrocephalus ex vacuo
becomes very important and is a challenging task.
Existing studies have largely focused on dierentiating pa-
tients with iNPH from healthy controls, but more researches
are being published to compare with patients with AD with al-
ready advanced ventriculomegaly.7,8 Parameters such as the de-
gree of the callosal angle (CA), width of the temporal horn, and
the Evans’ index (EI) have been presented to dierentiate the
brain imaging of iNPH from AD. However, these tools are con-
troversial and require more integrated research through a vari-
ety of brain imaging indicators.9,10 Dierent studies reported
varying diagnostic sensitivities and specicities of radiological
parameters and even controversial results concerning the most
commonly used radiological markers such as Evans’ Index (EI)
or callosal angle (CA).11,12 us, nding out more accurate and
reectable brain imaging parameters to distinguish between
iNPH and AD is necessary. Consequently, this study used brain
magnetic resonance imaging (MRI) to identify the neuroradio-
logical distinctions between iNPH and hydrocephalus ex vacuo
through the following nine neuroimaging parameters, which
have been commonly used in the study of radiological param-
eters comparing iNPH with AD: EI, degrees of the CA, nar-
rowing of the superior parietal sulci, height of the Sylvian ssure,
width of the temporal horn, dilation of the perihippocampal
ssure (PHF), presence of focally enlarged cerebral sulci, se-
verity of periventricular hyperintensities, and medial temporal
lobe atrophy scale. In addition, the usefulness of these combined
parameters in distinguishing iNPH from AD than each element
was looked into.
METHODS
Participants
Overall, 77 patients diagnosed with ventriculomegaly at SMG-
SNU Boramae Medical Center from January 2013 to December
2018 detected by MRI using an Evans’ ratio of at least 0.3 were
retrospectively recruited in this study. e Evans’ ratio is de-
ned as the maximum ventricular width divided by the largest
frontal distance between the inner tables of the skull. Patients
>85 and <55 years old, history of head injury, brain tumor or
cerebral infarction/hemorrhage, drug and alcohol abuse, and
Parkinson’s disease were the exclusion criteria. Of the 77 selected
patients, 29 patients with probable AD were diagnosed based
on the National Institute of Neurological and Communicative
Diseases and Stroke/Alzheimer’s Disease and Related Disorders
Association criteria.13 Moreover, 25 patients with probable iNPH
were identied based on the 2005 iNPH International Criteria
and the updated references based on these criteria.1 Probable
iNPH would typically have gait disturbance plus at least one
other area of impairment in cognition, urinary symptoms, or
both, and ventriculomegaly seen on brain imaging. ere were
23 subjects that could not be distinguished between the two
diseases; they were excluded from the study.
Standard protocol approvals, registrations, and
patient consents
is study was performed following the ethical standards
established in the 1964 Declaration of Helsinki and was ap-
proved by the Ethics Board of SMG-SNU Boramae Medical
Center (IRB No. 26-2014-42). All subjects or responsible care-
givers were waived from their informed consent by the IRB
of SMG-SNU Medical Center since this study was performed
retrospectively.
MRI analysis
In 54 patients (25 patients with iNPH and 29 patients with
AD), T1-weighted coronal MRI images were attained through
the 3.0-Tesla MRI scanner (Philips, Achieva, Harvey, IL, USA)
based on the following radiological parameters: repetition
time (9.9 ms), echo time (4.6 ms), ip angle (8°), eld of view
(220 mm), matrix size (220×220 pixels), and slice thickness
(1 mm). e axial T2-weighted uid-attenuated inversion re-
covery images were also attained. Two neuroradiologists rat-
ed each patient’s image without prior insight on the patient’s

M Kim et al.
www.psychiatryinvestigation.org 3
medical information. e radiologists reached a nal decision
aer a consensus meeting in case of discrepancies. Figure 1
shows the following radiological parameters evaluated: 1) the
EI14,15 (frontal horn diameter divided by inner skull diameter ob-
tained from the same transverse section); 2) degree of the CA16,17
(the angle between the lateral ventricles in the coronal plane
measured through the posterior commissure perpendicular to
the anteriorposterior commissure plane); 3) the narrowing
of the superior parietal sulci (the narrowing of sulci at high
convexity and medial parafalcine measured on the coronal
plane; 0=normal, 1=narrowing of sulci restricted in the para-
falcine, and 2=narrowing extended to the vertex);18 and 4)
the height of the Sylvian ssure (in millimeter; the height of the
Sylvian ssure was measured in ve coronal planes starting from
the coronal view where the midbrain began to emerge based
on the method described by Virhammar et al.19). e average
value of the ve dierent locations on both sides was record-
ed.19,20 Moreover, 5) the width of the temporal horn (in milli-
meter; the average of the maximal width of the right and le
temporal horns on the transverse plane was used);19 6) the se-
verity of the perihippocampal ssure (PHF) dilatation (the di-
lation of the PHF was subjectively measured on the transverse
A
D
G
B
E
H
C
F
I
Figure 1. MRI parameters. A: EI. B: Degrees of the callosal angle. C: Narrowing of the superior parietal sulci, graded as 2=vertex. D: Height
of the Sylvian ssure. E: Width of the temporal horn. F: Perihippocampal ssure dilatation, graded as 2=severe. G: Focally enlarged cere-
bral sulci, graded as 1=present. H: Periventricular hyperintensities, graded as 3=conuent areas. I: MTA scale, graded as 2.

4 Psychiatry Investig
AD and iNPH
and coronal planes; 0=none to mild, 1=moderate, and 2=se-
vere);21 7) the presence of focally enlarged cerebral sulci (the CSF
accumulation in focally enlarged cerebral sulcus was graded as
0=not present and 1=present);22,23 8) the severity of periven-
tricular hyperintensities (Fazekas scale; 1=caps or pencil-thin
lining, 2=smooth halo, and 3=irregular large symmetric hyper-
intensities extending out into the deep white matter region);24
and 9) Scheltens’ scale for medial temporal lobe atrophy (MTA
scale; 0=no atrophy, 1=widening of choroid ssure only, 2=wid-
ening of choroid ssure and temporal horn of lateral ventricle,
3=moderate loss of hippocampal volume (decrease in height),
and 4=severe hippocampal volume loss)25 were also measured.
Furthermore, the average of the le and right values was used
for all measurements.26
Statistical data analysis
For normally distributed continuous variables, univariate
generalized linear model statistical analyses were employed
for the between-group comparisons, including age and global
CDR as covariates. Logistic regression was used when the nor-
mal distribution was not satised, including age and global CDR
as covariates. Consequently, the cuto values of continuous
variables were determined using the receiver operating char-
acteristic (ROC) curve. All hypotheses tests were two-sided. Bi-
nary logistic analyses were performed to get composite score.
Statistical tests were conducted using Statistical Package for the
Social Sciences, version 24 (IBM Corp., Armonk, NY, USA).
e threshold of signicance was set at p<0.05 at both sides.
RESULTS
Participants
Table 1 presents demographic data for the 54 patients. e
mean age (SD) at the time of MRI was 72.32 (8.69) and 81.41
(4.81) years in the iNPH and hydrocephalus ex vacuo groups,
respectively. In addition, the dierence in age between the two
groups was statistically signicant (p<0.001). e global CDR
showed the signicant dierence between the two groups (p<
0.005), 0.66 (0.28), and 1.00 (0.52), respectively. However, the
other demographic data did not show a signicant dierence
between the two groups.
Dierences of radiological parameters in each group
e degree of the CA was smaller in the iNPH group than
in the AD group, showing 87.35±20.05 and 110.94±16.66 in
the iNPH and AD groups, respectively. e CA (p<0.05) and
height of the Sylvian ssure (p<0.05) showed statistically sig-
nicant dierences between the two groups (Table 2). Further-
more, 80% and 31% of the patients in the iNPH and hydroceph-
alus ex vacuo groups had normal PHF dilation, respectively
without statistical signicance dierence. However, Evans’ In-
dex was higher in iNPH group than Hydrocephalus ex vacuo
group, 0.38 (0.05) vs. 0.35 (0.29), respectively, without statisti-
cal signicance. Evans’ index and width of temporal horn were
greater in iNPH group than AD group, however, in this study
without statistical signicance. Absence of superior parietal
sulci narrowing was found in more patients with AD than pa-
tients with iNPH with statistically signicant dierence (p<
0.05) (Table 3).
ROC analysis and binary logistic regression analysis
An ROC analysis was conducted to establish a diagnostic cut-
o value for each of the above three variables, which displayed
Table 1. Demographic and cognitive characteristics of partici-
pants
Idiopathic
normal pressure
hydrocephalus
(N=25)
Hydrocephalus
ex vacuo (N=29) p
Age, years 72.32 (8.69)†81.41 (4.81)†<0.001
Sex, male, N (%)*17 (68) 21 (72.4) 0.72
Education, years 9.76 (4.22)†9.55 (6.16)†0.88
Global CDR 0.66 (0.28)†1.00 (0.52)†0.005
MMSE 20.60 (5.13)†18.34 (5.49)†0.13
*a Mann-Whitney U-test or a chi-squared test was used for com-
parisons, †mean (standard deviation). CDR: clinical dementia rat-
ing scale, MMSE: Mini-Mental State Exam
Table 2. Comparison of continuous radiological parameters between the idiopathic Normal Pressure Hydrocephalus and Hydrocephalus ex
vacuo group
Continuous variables Idiopathic normal pressure
hydrocephalus (N=25)
Hydrocephalus ex vacuo
(N=29) p*FPartial Eta squared
Evans’ index 0.38 (0.05)†0.35 (0.29)†0.07 3.50 0.07
Degrees of callosal angle (°) 87.36 (20.05)†110.94 (16.66)†0.01 6.99 0.12
Height of Sylvian ssure (mm) 27.19 (3.02)†25.41(3.04)†0.01 8.69 0.15
Width of temporal horn (mm) 9.01 (2.44)†8.34 (2.35)†0.51 0.45 0.01
*univariate generalized linear model analyses were conducted for the between-group comparisons, including age and clinical dementia rating
scale as covariates, †mean (standard deviation)

M Kim et al.
www.psychiatryinvestigation.org 5
statistically signicant dierences between the two groups (Fig-
ure 2). When maximizing sensitivity and specicity, the cut-
o values were as follows: CA, 89.8; height of the Sylvian s-
sure, 26.2; and narrowing of superior parietal sulci, 0/1. Based
on these values, iNPH could be dierentiated from hydroceph-
alus ex vacuo with a sensitivity of 0.90, 0.64, and 0.68, respective-
ly, and specicity of 0.64, 0.76, and 0.83, respectively. e area
under the curve (AUC) was 0.81, 0.65, and 0.79, respectively.
Table 3. Comparison of categorical radiological parameters between the idiopathic Normal Pressure Hydrocephalus and Hydrocephalus ex
vacuo group
Categorical variables
Idiopathic normal pressure
hydrocephalus
(N=25)
Hydrocephalus ex vacuo
(N=29) OR†
Superior parietal sulci narrowing
Normal 8 (32) 24 (82.8) 0.07*
Narrowing of sulci restricted in the parafalcine 4 (16) 4 (13.8) 0.15
Narrowing extended to the vertex 13 (52) 1 (3.4) 1
Perihippocampal ssure dilatation
None to mild 20 (80) 9 (31) 5.50
Moderate 2 (8) 10 (34.5) 1.07
Severe 3 (12) 10 (34.5) 1
Focally enlarged cerebral sulci
Not present 17 (68) 26 (89.7) 0.22
Present 8 (32) 3 (10.3) 1
Periventricular hyperintensities
Caps or pencil-thin lining 0 (0) 6 (20.7) 8.5e-10
Smooth halo 12 (48) 8 (27.6) 1.31
Irregular large symmetric hyperintensities extending out
into the deep white matter region
13 (52) 15 (51.7) 1
Medial temporal atrophy scale Le/right Le/right 5.69‡
No atrophy 1 (4)/1 (4) 0 (0)/0 (0)
Only widening of choroid ssure 3 (12)/3 (12) 0 (0)/0 (0)
Also widening of temporal horn of lateral ventricle 5 (20)/5 (20) 5 (17.2)/7 (24.1)
Moderate loss of hippocampal volume (decrease in height) 11 (44)/12 (48) 14 (48.3)/12 (41.4) 2.20
Severe volume loss of hippocampus 5 (20)/4 (16) 10 (34.5)/10 (34.5) 1
*p<0.05, †logistic regression was conducted, including age and CDR as covariates, ‡OR for groups of no atrophy, only widening of choroid s-
sure, and also widening of temporal horn of lateral ventricle in medial temporal atrophy scale, which were grouped as one category due to
small numbers for logistic statistical analysis. CDR: clinical dementia rating scale, OR: odds ratios
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
0.0 0.00.0
1-specicity 1-specicity1-specicity
0.2 0.20.20.4 0.40.40.6 0.60.60.8 0.8
0.81
0.79
0.65
0.81.0 1.01.0
Sensitivity
Sensitivity
Sensitivity
A CB
Figure 2. ROC curve to differentiate iNPH from hydrocephalus ex vacuo. A: Degrees of the callosal angle. B: Height of the Sylvian ssure.
C: Narrowing of superior parietal sulci. The AUC is shown. ROC: receiver operating curve, AUC: area under the curve, iNPH: idiopathic nor-
mal pressure hydrocephalus.

6 Psychiatry Investig
AD and iNPH
e binary logistic regression model was used to identify ra-
diological parameters from the aforementioned three mean-
ingful variables, which optimally dierentiated patients with
iNPH from patients with hydrocephalus ex vacuo to investigate
if the combination of these three factors is more useful in dis-
tinguishing iNPH from AD than each element. e nal model
included the absence of narrowing of superior parietal sulci
[exp(b)=0.296, p=0.024], narrow degree of the CA [exp(b)=
1.056, p=0.041], and height of the Sylvian ssure [exp(b)=0.745,
p=0.029]. Including these three variables into the model clas-
sied iNPH and hydrocephalus ex vacuo with an accuracy of
0.78. e rate of the explained variance according to Nagelker-
ke’s estimate for R2 27 was 0.58. Binary logistic regression yield-
ed a composite score dened as 0.055×CA-0.294×height of
the Sylvian ssure-1.218×narrowing of superior parietal sulci+
3.186. ROC analysis of this composite score showed an AUC,
sensitivity, and specicity of 0.89, 0.83, and 0.84, respectively
(Figure 3).
DISCUSSION
is study aims to evaluate and compare the radiological pa-
rameters of brain MRI between subjects with iNPH and AD
patients with hydrocephalus ex vacuo. When comparing the
radiological parameters, the degree of callosal angle (CA), the
height of the Sylvian ssure and narrowing of superior parietal
sulci, which are statistically signicant variables, would be use-
ful for comparing the two groups (Figure 4).
e degree of the CA was smaller in the iNPH group than
in the AD group, showing 87.35±20.05 and 110.94±16.66 in
the iNPH and AD groups, respectively. is result was similar
to the ndings of other previous studies. In a study by Ishii et
al.,17 the CA in the iNPH group (mean±SD, 66±14) was sig-
nicantly smaller than that in the AD group (104±15), and the
cuto value was 90. Unlike the AD, iNPH lls the ventricles
with the CSF pressure on the upper part of the brain, causing
small CA, which may indicate ventriculomegaly. In contrast,
diuse brain atrophy such as in AD causes wider CA. However,
the widening of the temporal horn cannot dierentiate iNPH
from hydrocephalus ex vacuo. Regarding the lack of dierenc-
es in the width of the temporal horn between the iNPH and
AD groups in this study, the temporal lobe atrophy may result
in the widening of the temporal horn similar to iNPH.
Evans’ Index could be used as the radiological parameter of
iNPH since the ventricular enlargement may not be entirely at-
tributable to cerebral atrophy as AD although it has high sen-
sitivity but low specicity for iNPH. In this study, Evans’ Index
showed no statistical signicant dierence between the two
groups. Absence of narrowing of superior parietal sulci (grade
0=normal) was statistically signicant aer controlling age and
global CDR (Table 3). Due to diuse brain atrophy such as AD,
absence of narrowing of superior parietal sulci would mani-
fest in AD. Unlike AD, iNPH could show the narrowing of su-
perior parietal sulci as the ventriculomegaly progresses.
e height of the Sylvian ssure in this study showed the dif-
ference between the two groups. e combination of the Sylvi-
an ssure widening and the narrowing at the vertex has been
termed disproportionately enlarged subarachnoid space hydro-
cephalus (DESH), reecting the disproportionality of the CSF
between the superior and inferior CSF spaces,10 which would
be the typical sign of iNPH. Among the signs of DESH, the wid-
ening of the inferior CSF, such as the Sylvian ssure widening,
1.0
0.8
0.6
0.4
0.2
0.0
0.0
1-specicity
ROC curve
0.2 0.4 0.6 0.8
0.89
1.0
Sensitivity
Figure 3. ROC of the composite score to differentiate iNPH from
hydrocephalus ex vacuo. ROC analysis of this composite score
showed an AUC of 0.89. ROC: receiver operating curve, AUC:
area under the curve, iNPH: idiopathic normal pressure hydro-
cephalus.
Figure 4. MRI images of the idiopathic normal pressure hydro-
cephalus and hydrocephalus ex vacuo. The image on the left
represents iNPH, showing a small callosal angle (CA), dilatation
of the Sylvian fissure, and narrowing of superior parietal sulci.
The image on the right represents hydrocephalus ex vacuo with a
large CA, no dilatation of the Sylvian ssure, and absence of nar-
rowing of superior parietal sulci. iNPH: idiopathic normal pressure
hydrocephalus.

M Kim et al.
www.psychiatryinvestigation.org 7
may dierentiate iNPH from hydrocephalus ex vacuo, In the
temporal lobe, the typical sign of iNPH may be the dilatation of
the temporal horn due to CSF increase. However, in this study,
the width of the temporal horn was not statistically dierent
between the two groups. e PHF is not dilated in iNPH and
is sometimes compressed because no communication exists
between the temporal horn and the PHF through the choroid
plexus.28 But, the dilatation of the PHF was not statistically dif-
ferent between hydrocephalus ex vacuo and NPH.
No dierences exist between the two groups in the presence
of focally enlarged cerebral sulcus and the severity of periven-
tricular hyperintensities. White matter changes, including peri-
ventricular and deep white matter hyperintensity, are common
in patients with iNPH and AD. Barber et al.29 accentuated that
periventricular hyperintensities displayed positive correlations
with age and were prominent not only in vascular dementia but
also in AD. According to a previous study, periventricular white
matter hyperintensities correspond to the loss, demyelination,
and gliosis of ependymal lining induced by ventricular enlarge-
ment,30 prompting abnormal hydrodynamic changes in the CSF
and an increase in the water content of the white matter.31-33
e induction of compensatory CSF ow into the periventric-
ular white matter region via the pathological disruption of the
ependyma is similar, although the mechanisms of ventricular
enlargement may dier between iNPH and AD. is similar-
ity explains the presence of periventricular white matter hyper-
intensities in both patients with AD and iNPH when examined
through MRI.
Kitagaki et al.20 reported the presence of a few sulci dilations
that allows distinguishing between patients with AD and iNPH.
However, the severity of focally enlarged cerebral sulci param-
eters in the present study did not show any statistically signi-
cant dierences between patients with AD with ventriculo-
megaly and patients with iNPH (p=0.20). is may be because
focally dilated sulci are not a common feature in iNPH. In this
study, only 32% of patients with iNPH had focally dilated sulci;
this is similar to a study by Hashimoto et al.,34 which reported
29%. is suggests that focally dilated sulci are not reliable im-
aging markers for iNPH diagnosis.
Since the diagnosis of iNPH is complicated by the variabil-
ity existing in its clinical presentation and course, both clinical
ndings and radiological parameters would be much more
helpful for the correct diagnosis of iNPH. e radiological pa-
rameters hold the signicance as the noninvasive technique to
distinguish various diseases such as AD. e composite scores
generated from the logistic regression results of the degree of
the CA, the height of the Sylvian ssure and narrowing of su-
perior parietal sulci, which are statistically signicant variables,
would be useful for comparing the two groups (AUC, 0.89).
is study has several limitations. First, problems in gener-
alizing the results of this study exist because the subjects were
retrospectively recruited at one hospital. Second, the diagnosis
of iNPH and AD relied upon clinical diagnostic criteria. e
use of amyloid PET would have provided a more accurate di-
agnosis for patients with hydrocephalus ex vacuo, although the
diagnostic uncertainty between the NPH and AD was exclud-
ed. ird, due to lack of technological support, the computer
analyses in the brain MRI imaging was not used. In addition,
the power of the study may be low because of the small over-
all sample size. us, a larger study is needed in the future.
e ndings of this study suggest that narrowing of the CA,
dilatation of the Sylvian ssure and narrowing of superior pa-
rietal sulci may be used as reliable radiological markers to dif-
ferentiate patients with iNPH from those with hydrocephalus
ex vacuo. e composite score using narrowing of the CA, dil-
atation of the Sylvian ssure and narrowing of superior parietal
sulci in the brain MRI, combined with clinical ndings would
be helpful in distinguishing iNPH with AD.
Availability of data and materials
e datasets used and/or analyzed during the current study
are available from the corresponding author on reasonable
request.
Acknowledgments
Supported by grant no. 26-2014-42 from the SK Telecom Research Fund.
Conflicts of Interest
e authors have no potential conicts of interest to disclose.
Author Contributions
Conceptualization: Sun-Won Park, Jun-Young Lee, Jee-Young Lee, Hw-
ancheol Son, Yu Kyeong Kim, Sang Hyung Lee. Data curation: Minkyung
Kim, Sun-Won Park, Hongrae Kim, Jung Hyo Rhim. Formal analysis:
Minkyung Kim, Sun-Won Park, Hongrae Kim, Jung Hyo Rhim. Funding
acquisition: Sang Hyung Lee. Methodology: Sun-Won Park, Jun-Young
Lee, Soowon Park, Sang Hyung Lee. Writing—original dra: Minkyung
Kim, Hongrae Kim, Jun-Young Lee. Writing—review & editing: Minkyung
Kim, Sun-Won Park, Jun-Young Lee, Jung Hyo Rhim, Soowon Park, Jee-
Young Lee, Hwancheol Son, Yu Kyeong Kim, Sang Hyung Lee.
ORCID iDs
Minkyung Kim https://orcid.org/0000-0001-6282-5612
Sun-Won Park https://orcid.org/0000-0002-5063-2685
Jun-Young Lee https://orcid.org/0000-0002-5893-3124
Hongrae Kim https://orcid.org/0000-0002-9319-7521
Jung Hyo Rhim https://orcid.org/0000-0001-5822-9770
Soowon Park https://orcid.org/0000-0002-3348-940X
Jee-Young Lee https://orcid.org/0000-0002-9120-2075
Hwancheol Son https://orcid.org/0000-0001-5033-0153
Yu Kyeong Kim https://orcid.org/0000-0002-3282-822X
Sang Hyung Lee https://orcid.org/0000-0003-4720-955X
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