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Proton MR spectroscopy and white matter hyperintensities in
idiopathic normal pressure hydrocephalus and other dementias
1
O ALGIN, MD,
2
B HAKYEMEZ, MD and
2
M PARLAK, MD
1
Atatu¨ rk Training and Education Hospital, Radiology Department, Ankara, Turkey and
2
Department of Radiology,
Uludag University Medical Faculty, Gorukle, Bursa, Turkey
ABSTRACT. The differentiation of idiopathic normal-pressure hydrocephalus (INPH) from
other types of dementia is a clinical challenge. The aim of this prospective study was to
evaluate the role of proton MR spectroscopy (MRS) and white matter hyperintensities
(WMH) in the diagnosis of INPH, predicting response to therapy and differentiating INPH
from other dementias. The study included 18 patients with INPH (Group 1), 11 patients
with other types of dementia (Group 2) and 20 control patients (Group 3). The value of
WMH scores and MRS findings in diagnosis, evaluation of response to therapy and in the
differentiation of INPH from other dementias was statistically evaluated. The level of
statistical significance was set at p,0.05 (Kruskal–Wallis and Mann–Whitney U-test). In
both Groups 1 and 2, N-acetylaspartate (NAA)/choline-NAA/creatine ratios were
significantly less than in the control group (p,0.05). The WMH and MRS findings of
Groups 1 and 2 demonstrated no statistically significant correlation (p.0.05). No
correlation was found between the outcome of shunt operations and WMH and MRS
findings (p.0.05). In conclusion, neither WMH nor MRS were useful in differentiating
INPH from other types of dementia. WMH and MRS showed no additional benefit in
identifying INPH patients who will better respond to shunt therapy.
Received 10 May 2009
Revised 12 August 2009
Accepted 24 August 2009
DOI: 10.1259/bjr/43131041
’2010 The British Institute of
Radiology
Idiopathic normal-pressure hydrocephalus (INPH) is
a rare disease affecting the elderly [1]. The exact aetiol-
ogy of the disease is unknown and the most common
symptoms are dementia, gait apraxia and urinary
incontinence [1, 2]. INPH differs from other dementias
in that the symptoms can show regression with
cerebrospinal fluid (CSF) diversion [2, 3]. This opportu-
nity for treatment makes it important to differentiate
INPH from other dementias that cause senile changes,
vascular disease and Alzheimer’s [3, 4].
Manytestshavebeenemployedinthediagnosisof
INPH, including CSF pressure measurements, intrathecal
saline infusion tests, intermittent CSF drainage, cerebral
blood flow (CBF) measurements and brain biopsy [3]. In
addition, imaging methods such as radionuclide cisterno-
graphy, CT, MRI, CT cisternography, phase-contrast cine
MRI and perfusion MRI have also been used [5–7].
Treatment options for INPH include third ventriculostomy,
ventriculoperitoneal shunt (VPS) or lumboperitoneal shunt
procedures [8]. The success rate of shunt therapies varies
between 30% and 65% [9–12].
Some reports have emphasised that subcortical and deep
white matter hyperintensities (WMH) on T
2
weighted
images are more common in patients with INPH [2, 11].
This finding is attributed to ischaemia of small vessels
owing to low CBF [2, 13]. Also, recent studies have reported
a relationship between WMH and vascular compliance and
pulsation defects [14]. Some authors suggest that the
response to shunt therapy is worse in patients with
WMH, while others propose the opposite [2, 7, 11, 15].
Proton MR spectroscopy (MRS) is a non-invasive
technique that images some of the metabolites in brain
tissue [16, 17]. Although MRS is commonly used in
differentiating a variety of brain lesions, the number of
articles evaluating its efficacy in the diagnosis of INPH is
limited [10, 18–21]. MRS can aid in analysing the severity
of neuronal injury before the treatment and effects of
shunt therapy [21]. N-acetylaspartate (NAA) is a meta-
bolite mainly found in neurons and is accepted as the
neuronal marker [4, 16, 17]. A decrease in NAA levels
shows neuronal injury and loss, as the regeneration
capacity of the neurons is limited [18, 20]. In the other
dementia syndromes, the NAA peak decreases irrever-
sibly [18–21]. By contrast, in INPH, although cerebral
functions can deteriorate because of ventriculomegaly,
minimal NAA decrease or neuronal loss is observed [21].
This finding implies that cerebral injury is reversible.
The aim of this study was to evaluate both the efficacy
of MRS and the quantification of WMH in the differential
diagnosis of INPH from other causes of dementia. We
also hoped to assess the ability of these approaches to
predict response to therapy.
Methods and materials
Patient population
Patients suffering from dementia who were sent to our
department for routine MRI were included in the study.
Address correspondence to: Oktay Algin, Department of Radiology,
Uludag University Medical Faculty, Gorukle, Bursa, Turkey. E-mail:
droktayalgin@gmail.com
This study has been presented as a poster presentation at the 33
rd
European Society of Neuroradiology Annual Meeting held in
Crakow, in 18–21, September 2008.
The British Journal of Radiology, 83 (2010), 747–752
The British Journal of Radiology, September 2010 747
MRS was added to the imaging protocol and both MRS
and routine MRI findings were prospectively evaluated.
Three groups of patients were identified. Group 1
comprised patients diagnosed as having probable INPH
on the basis of clinical, laboratory and radiological
findings, as well as on spinal tap tests. Group 2 patients
were those on routine clinical follow-up owing to other
dementias (senile, vascular, dementia due to Alzheimer’s
disease) [12]. The diagnosis of dementia was confirmed in
both groups with neuropsychological tests. An experi-
enced neurologist (OT) and neuroradiologist (BH)
decided the grouping of patients in consensus based on
their diagnoses according to clinical guidelines for INPH
[12]. The control group (Group 3) comprised patients of
the same age who had MRI scans in response to headache.
The number of patients included in each group was as
follows: Group 1, 18 patients (8 males, 10 females; mean age
66 years, age range 50–75 years); Group 2, 11 patients (6
males, 5 females; mean age 64 years, age range 45–79
years); Group 3, 20 patients (10 males, 10 females; mean age
53 years, age range 40–75 years) (Table 1). The patients
included in the control group had no pathological findings
or any additional illnesses. Patients under 40 years of age
were not included in the control group, as INPH mainly
affects the elderly. Patients with trauma, depression,
malignancy, intracranial mass lesion, bleeding, obstructive
hydrocephalus or intracranial infectious disease were also
excluded from the study. All of the patients in Groups 1
and 2 had at least two of the following symptoms: urinary
incontinence, dementia or apraxia. The Evans index was
calculated for each patient by dividing the maximum
width between the frontal horns of by the lateral ventricles
to the length between the two inner tabulae [6]. Patients
with an Evans index ,0.30 were not included in either
Group 1 or 2. Informed consent was taken from all patients
before the examination. The study was approved by the
ethics committee of our university.
Imaging procedures
Brain MRI examinations were performed in a 1.5 T MR
device (Magnetom Vision Plus; Siemens, Erlangen,
Germany) with a standard head coil according to the
following MRI protocol: fluid attenuated inversion
recovery (FLAIR) axial plane (time to repeat (TR)/time
to echo (TE) 8400/114; time interval (TI) 2150 msn; field
of view (FOV) 230; matrix 2566256), T
1
weighted spin-
echo (SE) axial and sagittal planes (TR/TE 550/18;
matrix 1926256; FOV 230; 4 mm slice thickness and
1 mm slice gap) and T
2
weighted turbo spin-echo (TSE)
axial and coronal planes (TR/TE 5400/99; FOV 230 mm;
matrix 3456512; slice thickness 2 mm) were applied.
Following these sequences, MRS using position resolved
spectroscopy (PRESS) sequence was performed by
placing an 8 cm
3
VOI (volume of interest) in the frontal
lobe neighbouring the frontal horn of lateral ventricle
(TE/TR 135/2000; NEX 136) (Figure 1). The total
examination duration of all sequences was about 20 min.
Following the acquisition of all images, MRS findings in
addition to routine MRI findings were evaluated by two
radiologists (OA, MP) blind to the clinical and laboratory
data at the workstation of our MR unit. Ratios of NAA,
choline (Cho) and creatine (Cr) peaks were calculated.
WMH at the lateral ventricular and supraventricular
levels detected on FLAIR and T
2
weighted images were
scored visually according to the grading system:
NGrade 1: less than 25% of white matter affected.
NGrade 2: 25–50% of white matter affected.
NGrade 3: 50–75% of white matter affected.
NGrade 4: more than 75% of white matter affected.
Patients in Group 1 were followed clinically for 1 year
to assess shunt responsiveness. To evaluate predictors of
outcome, treatment response to CSF diversion was
defined as improvement in at least one symptom of
INPH (definite INPH). MR and MRS findings of all
patients were compared with clinical and laboratory
examinations, as well as post-operative outcomes. The
contribution of the findings to the diagnosis and therapy
was statistically analysed.
Statistical analysis
All statistical analysis was performed with SPSS 13.0
software (SPSS Inc., Chicago, IL). The concordance of the
data to the normal variation was evaluated with the
Shapiro–Wilk test. The results from all three groups were
compared with Kruskal–Wallis x
2
tests. The relationship
between two groups was evaluated with the Mann–
Whitney U-test. The level of statistical significance was
set at p,0.05.
Results
The Evans indices of all patients in Groups 1 and 2 were
.0.3. The mean Mini-mental State Examination (MMSE)
scores in Groups 1 and 2 were 18.6 (range 15–22) and 17.3
(range 15–20), respectively. All patients in Groups 1 and 2
had dementia. All patients in Group 1 and 9 out of 11
patients in Group 2 had gait apraxia. Urinary incontinence
was present in 14 out of 18 patientsin Group 1, whereas 10
out of 11 patients in Group 2 were incontinent. There was
no statistically significant difference between the presence
of symptoms and each group (p.0.05). In Group 1, 12
(67%) patients improved following VPS operation; the
remaining 6 patients (33%) did not improve (Table 2).
There was no statistical significance between the presence
of symptoms and the response to the shunt surgery in
INPH patients (p.0.05).
WMH was increased in both Groups 1 and 2, although
no statistically significant difference was found between
Table 1. Demographic characteristics of the three patient
groups
INPH OD Controls
Group 1 Group 2 Group 3
Number of cases
(female/male)
18 (10/8) 11 (5/6) 20 (10/10)
Mean age, years
(range)
66 (50–75) 64 (45–79) 53 (40–75)
INPH, idiopathic normaly-pressure hydrocephalus; OD, other
dementias.
O Algin, B Hakyemez and M Parlak
748 The British Journal of Radiology, September 2010
all three groups or between two of the groups (p.0.05)
(Figure 2). There was no correlation between WMH and
the response to shunt operation (p.0.05) (Table 3).
In Groups 1 and 2, NAA/Cho ratios were significantly
less than for the control group (p,0.05) (Figure 3). In
patients with INPH, NAA/Cr ratios were significantly
less than for the control group (p50.001). NAA/Cr ratios
in the other patients with dementia were less than the
control group (p,0.05). In Groups 1 and 2 no statistically
significant difference between NAA/Cho and NAA/Cr
ratios was detected (p.0.05). Likewise, no significant
correlation was detected between the NAA/Cho and
NAA/Cr ratios and response of patients with INPH to
the shunt procedure (p.0.05) (Table 3).
Although Cho/Cr ratios in Groups 1 and 2 were
increased compared with controls, this increase was not
statistically significant. No correlation was found
between Cho/Cr ratios and the response to shunt
procedure (p.0.05) (Table 3).
Discussion
INPH is a rare disease usually affecting the elderly
[1, 13]. This condition can be either idiopathic or secon-
dary (SNPH) to subarachnoid haemorrhage, meningitis,
cranial trauma or intracranial surgery [1–3]. INPH is
characterised by gait disturbance, dementia and/or
urinary incontinence. Normal opening pressure was
observed at lumbar puncture in patients without
causative disorders and ventricular enlargement was
seen owing to disturbed CSF circulation [9–15].
Many pathophysiological changes occur in INPH in
addition to ventriculomegaly [2, 22]. Other findings are
increased resistance to CSF reabsorption, hyperdynamic
aqueductal CSF flow, decrease in intracranial compli-
ance, increased CSF pulse pressure with normal CSF
pressure and decreased CBF [5, 14]. As yet, no theory has
been proposed to explain all these changes [23]. It is
assumed that the decrease in CBF forms the basis of the
pathophysiological changes [24–26]. By contrast, alter-
native theories support the decrease in intracranial
compliance or the changes in spread of pulse waves
[14, 22, 27–29]. As a result, INPH can be accepted as a
complex pathology with many different contributing
factors [2, 23].
MRS is a technique commonly used in the differentia-
tion of brain tumours, cerebrovascular diseases, post-
radiotherapy changes, intracranial abscesses and degen-
erative diseases [4, 16, 17]. The NAA concentration in the
brain is used as a neuronal marker [19]. Only a limited
number of published studies have evaluated the role of
MRS in INPH [10, 18]. It has been reported that NAA
levels decrease in patients with INPH [20, 27]. Our study
supports this observation. Shiino et al [10] postulated
that the effectiveness of shunt procedures could be
predicted by NAA/Cr and NAA/Cho ratios; in this
study, it was reported that patients with decreased NAA
Figure 1. Representative (a) axial, (b) sagittal T
1
weighted and (c) coronal T
2
weighted MR spectroscopy images. The black
rectangles indicate the region of interest for MR spectroscopy. To achieve a reproducible position, the voxels were placed in the
same regions in all patients and controls.
Table 2. Symptoms and shunt outcomes of patients with
probable INPH (Group 1)
No.
(M/F)
Age
(years)
Gait
apraxia
Urinary
incontinence
Dementia Shunt
outcome
1 (F) 75 ++ + +
2 (F) 63 ++ + 2
3 (M) 65 ++ + 2
4 (M) 70 +2++
5 (M) 66 ++ + +
6 (M) 66 ++ + +
7 (F) 68 ++ + +
8 (F) 50 +2+2
9 (M) 50 +2++
10 (F) 75 ++ + +
11 (F) 70 +2++
12 (M) 73 ++ + 2
13 (M) 59 ++ + 2
14 (F) 60 ++ + 2
15 (M) 73 ++ + +
16 (F) 57 ++ + +
17 (F) 74 ++ + +
18 (F) 72 ++ + +
INPH, idiopathic normal-pressure hydrocephalus; M/F, male/
female.
MR spectroscopy in INPH and other dementias
The British Journal of Radiology, September 2010 749
in the white matter show poor response to shunt therapy,
owing to irreversible neuronal damage. By contrast,
patients with high NAA/Cr and NAA/Cho ratios prior
to treatment responded well. In our study, decreased
NAA/Cr and NAA/Cho ratios were detected in INPH
patients, but no statistically significant correlation with
the response to shunt therapy was found. Our MRS
findings also show that there is neuronal loss of the brain
parenchyma in patients with INPH; this could be a
consequence of various factors such as ischaemia,
degeneration or mechanical stress. MRS, although not
sufficient alone to diagnose INPH or to differentiate it
from other causes of dementia, can be used as an adjunct
tool to other MRI techniques.
Although in many studies the pathophysiology of
INPH has centred on cerebral ischaemia, ischaemia is not
present in all cases [22, 24–28]. Mathew et al [30]
proposed that dilation of lateral ventricles decreases
the flow in anterior cerebral arteries owing to stretching
of the vessels. Ventricular expansion forms a pressure
over venous structures and capillaries by increasing
parenchymal pressure. It can also be postulated that
narrowing of arterioles due to ageing can increase white
matter ischaemia and the frequency of INPH [2, 14, 28–
31]. As a result of decreasing CBF, venous return and
CSF absorption via the transependymal–transvenous
route decreases [28, 31]. In their study with MRI and
positron emission tomography (PET), Owler et al [32]
reported that CBF is decreased by 19% in patients with
INPH when compared with the control group; however,
the standard deviation of the data is high and CBF is
normal in 16% of patients with INPH. The CBF
measurements in patients with INPH and the control
group suggest that ischaemia is not a prerequisite for the
generation of INPH [5, 28]. It is not known if the
ischaemia is the cause or the effect of the disease [23, 27].
The general concept is that decreased CBF causes
neuronal loss [2, 26]. In the literature, it is reported that
CBF is normal in 15% of patients with INPH [5, 33]. In
patients with low CBF (global ischaemia), shunt proce-
dures do not always increase CBF and no significant
correlation has been shown between the relief of
symptoms and CBF [5]. In our study, the decrease in
NAA/Cho and NAA/Cr ratios could be a result of
neuronal loss owing to various factors (e.g. cerebral
ischaemia). As the same findings can be interpreted in
the other dementia patients, this finding is not specific to
INPH.
The WMH encountered in T
2
weighted and FLAIR
images of patients with INPH can be evaluated in two
groups: hyperintensities of the periventricular area
(PVH) and deep white matter hyperintensities
(DWMH) [34, 35]. PVH and DWMH are related to
periventricular oedema and ischaemic white matter
degeneration [2, 11, 28]. The predictive value of PVH
and DWMH in the diagnosis of INPH is not clear and no
direct statistical relationship has been detected [35, 36].
Our results are in good correlation with the literature
and no statistically significant relationship was detected
between INPH and WMH. This result shows that the
evaluation of WMH is not useful in differentiating INPH
from other causes of dementia. As reported in the
Figure 2. Scoring of the white matter hyperintensities (WMH) in axial T
2
weighted images of three patients: (a) Grade 1, (b)
Grade 3 and (c) Grade 4 (case with vascular dementia). Cases in (a, b) were diagnosed as idiopathic normal pressure
hydrocephalus.
Table 3. MR spectroscopy findings and WMH of the three patient groups
INPH
(Group 1)
OD
(Group 2)
Controls
(Group 3)
Among
groups
INPH vs
controls
INPH
vs OD
OD vs
controls
Shunt
response
NAA/Cho 1.38¡0.47 1.33¡0.25 1.68¡0.38 p,0.05 p,0.05 NS p,0.05 NS
NAA/Cr 1.51¡0.27 1.78¡0.65 2.2¡0.9 p,0.05 p50.001 NS p,0.05 NS
Cho/Cr 1.31¡0.65 1.54¡0.68 1.17¡0.37 NS NS NS NS NS
WMH 1.61¡0.97 2¡0.89 1.2¡0.95 NS NS NS NS NS
Cho, choline; Cr, creatine; INPH, idiopathic normal pressure hydrocephalus; OD, other dementias; NAA, N-acetylaspartate; NS,
not significant; WMH, white matter hyperintensities.
O Algin, B Hakyemez and M Parlak
750 The British Journal of Radiology, September 2010
literature, WMH can be encountered in the normal
ageing process [2, 11, 14, 35]. In our study, Grade 2 and
above WMH was found in 7 of 20 cases of the control
group. As a result, the detection of WMH in a patient is
not helpful for excluding the INPH diagnosis. In the
literature it is reported that there is a negative correlation
between the presence of PVH and DWMH and that their
presence cannot be used as a determinant to abandon the
shunt procedure [15, 34, 36]. In our study, we did not
find any correlation between WMH and response to
shunt procedure. As a result, we propose that the
presence of WMH cannot be used as a criterion to
preclude the shunt procedure.
The major limitation of our study is that there is no
gold standard method for definite INPH diagnosis [12].
As a result, false-negative and false-positive values for
the parameters evaluated in this study could not be
detected. TE values of MRS examinations were rela-
tively long and we could not measure values for all
metabolites (e.g. myoinositol). Myoinositol/Cr levels
are elevated in dementias that are pathologically
characterised by gliosis, such as Alzheimer’s disease
[4]. The use of a longer TE in the MRS acquisition
(rather than TE 30–35) precludes the possibility of
observing myoinisitol. Another limitation of our study
is that the response to shunt therapy is evaluated with
subjective criteria. As MRS images were acquired using
the single-voxel technique, and only in frontal lobes,
other brain areas and basal ganglia were not evaluated.
Taking the aetiology of INPH into consideration, the
neuronal injury in these other anatomical locations
should also be assessed. We could not perform multi-
voxel spectroscopy in all cases owing to technical
limitations. New studies evaluating the brain in a more
global fashion with multivoxel spectroscopy are war-
ranted.
One reason for the many conflicting findings in INPH
diagnosis could be the difficulty in differentiating more
acute and treatable cases from chronic cases with
irreversible neuronal loss. Most of the patients included
in the study were referred to our department from other
hospitals; thus, we could not obtain previous detailed
clinical and laboratory data. For this reason, it was not
possible to classify patients with dementia as acute–
chronic onset or minimal–moderate–severe. Multidiscipli-
nary large studies correlating these data with MRS and
WMH are needed.
Conclusion
Despite increasing efforts in this area over the past few
years, the development, hydrodynamic properties, ima-
ging findings, diagnosis and treatment of INPH are not
fully understood. Unfortunately, in many healthcare
centres, the differential diagnosis of INPH from other
causes of dementia by clinical characteristics is estab-
lished according to the results of the invasive shunt
operation. WMH was not useful in differentiating INPH
from other types of dementia. MRS can demonstrate
some pathological changes in patients with INPH, but is
not sufficient alone to establish the differential diagnosis.
MRS can be used as an adjunct tool to other imaging
modalities. WMH and MRS showed no extra benefit in
identifying INPH patients who will better-respond to
shunt therapy. New studies aimed at developing non-
invasive tests for both the diagnosis and evaluation of
response to therapy of INPH are warranted.
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