The role of perfusion and diffusion MRI in the assessment of patients affected by probable idiopathic normal pressure hydrocephalus. A cohort-prospective preliminary study
Tuniz et al. Fluids Barriers CNS
The role of perfusion and diffusion MRI in the assessment of patients affected by probable idiopathic normal pressure hydrocephalus. A cohort-prospective preliminary study
Francesco Tuniz 0
Maria Caterina Vescovi 0
Daniele Bagatto 2
Daniela Drigo 1
Maria Cristina De Colle 2
Marta Maieron 3
Miran Skrap 0
0 Department of Neurosurgery, AOU-UD “Santa Maria della Misericordia” , Piazzale S.M. della Misericordia, 33100 Udine , Italy
1 Institute of Epidemiology, AOU-UD “Santa Maria della Misericordia” , Udine , Italy
2 Department of Neuroradiology, AOU-UD “Santa Maria della Misericordia” , Udine , Italy
3 Department of Physics, AOU-UD “Santa Maria della Misericordia” , Udine , Italy
Background: Invasive tests measuring resistance to cerebral spinal fluid (CSF) outflow and the effect of temporary drainage of CSF are used to select candidates affected by idiopathic normal pressure hydrocephalus (iNPH) for shunt surgery. Neither test, however, completely excludes patients from treatment. Perfusion and diffusion magnetic resonance imaging (MRI) are non-invasive techniques that might be of value in selecting patients for surgical treatment and understanding brain changes in iNPH patients. The aim of this study was to understand the role of perfusion and diffusion MRI in selecting candidates for shunt surgery and to investigate the relationship between cerebral perfusion and possible microstructural changes in brain tissue before and after invasive tests, and after ventricular-peritoneal (VP) shunt implantation, to better clarify pathophysiological mechanisms underlying iNPH. Methods: Twenty-three consecutive patients with probable iNPH were included in this study. Patients underwent a clinical and neuroradiological evaluation before and after invasive tests, and after surgery. Only patients who showed a positive result in at least one of the invasive tests were submitted for VP shunt implantation. Perfusion and diffusion magnetic resonance imaging (MRI) was performed before and after invasive tests and after shunt surgery. Results: Thirteen patients underwent surgery and all showed clinical improvement after VP shunt implantation and a significant increase in perfusion in both periventricular white matter (PVWM) and basal ganglia (BG) regions. The 10 patients that did not have surgery showed after invasive tests, a significant reduction in perfusion in both PVWM and BG regions. Comparing the changes in perfusion with those of diffusion in positive patients we found a significant positive correlation in BG and a significant inverse correlation in PVWM area. Conclusions: Perfusion MRI is a non-invasive technique that could be useful together with invasive tests in selecting patients for surgical treatment. Furthermore, the relationship between perfusion and diffusion data could better clarify pathophysiological mechanisms underlying iNPH. In PVWM area we suggest that interstitial edema could reduce microvascular blood flow and interfere with the blood supply to these regions. In BG regions we suggest that a chronic hypoxic insult caused by blood hypo-perfusion produces a chronic cytotoxic edema. Both in PVWM and in BG regions, pathophysiological mechanisms could be modified after VP-shunt implantation.
Diffusion; Hydrocephalus; iNPH; MRI; Perfusion; Shunt
Idiopathic normal pressure hydrocephalus (iNPH) is a
condition characterized by ventricular enlargement and
normal intracranial pressure (ICP) caused by disturbed
cerebral spinal fluid (CSF) dynamics [
]. The cause is
still unknown. The iNPH signs are typically subcortical,
characterized by slow progressive impairment of gait
and balance, cognitive deterioration and urinary
]. Treatment of iNPH patients with
ventricularperitoneal or ventricular-atrial shunts is successful, with
an improvement rate of more than 80% in recent
shortterm studies, and an acceptable complication rate [
At present, clinicians have two invasive predictive tests
to select patient candidates for surgery: a test
measuring compliance of craniospinal space or resistance to CSF
outflow (Rout), and a test measuring the effect on
symptoms of temporary drainage of CSF (CSF tap test) [
These tests are, however, not totally specific or sensitive
and can be used for selecting patients for shunt surgery
but not for excluding patients from treatment [
Better methods for the identification of responders and
non-responders are required. Cerebral blood flow (CBF)
is reduced in iNPH patients, mainly in the frontal cortex
and in accordance with the subcortical symptomatology,
in the basal ganglia, in the thalami and also in the
periventricular white matter (PVWM) [
]. As the
subcortical and periventricular regions seem to be of special
interest in iNPH, magnetic resonance (MR) perfusion
imaging with its relatively high resolution and sensitivity
for deep structures might be of value as a diagnostic and
predictive tool . Some authors have also investigated
the role of diffusion MRI in determining brain
parenchymal damage in PVWM and basal ganglia (BG) areas and
the role of apparent diffusion coefficient (ADC) in
predicting surgical outcome [
The aims of this study were to investigate (a) the
relationship between cerebral perfusion and microstructural
damage of brain tissue as measured by perfusion and
diffusion MRI in PVWM and BG areas before, after invasive
tests, and after surgery and (b) the potential role of
perfusion and diffusion MRI in selecting patients for VP-shunt
Patients selection and clinical evaluation
Twenty-three patients diagnosed with probable iNPH
were prospectively included between January 2013
and December 2014. Inclusion criteria for probable
iNPH were based on iNPH Guidelines: presence of a
gait disturbance in combination with cognitive and/
or urinary symptoms and an Evans’ Index > 0.30 in the
absence of any known cause for secondary
]. All patients underwent neuropsychological,
physiotherapeutic and neurological examinations, and
performance was assessed in the four domains of gait,
neuropsychology, balance and continence, yielding
separate scores as well as a total score on a recently published
iNPH scale [
]. Domain and total scores all range from 0
to 100 with 0 representing the most severe condition and
100 representing normal performance among healthy
individuals aged 70–74. This study was approved by our
Institutional Review Board and an informed consent was
acquired from each patient involved in this study.
A lumbar infusion test and a tap test were performed on
each patient in same procedure. Lumbar puncture was
performed in the morning and mean CSF basal
pressure was recorded. A lumbar infusion test was then
performed using the constant rate infusion method and
Rout was calculated. After the infusion test was
completed, CSF was drained until the pressure returned to
baseline. Then, a tap test was performed, draining 50 ml
of CSF. A value of Rout greater than 13 mmHg/min/
ml was considered a predictor for good outcome after
shunt implantation [
], as well as a good response
to the CSF tap test. The response to CSF tap test was
expressed as the mean of the percentage change in all
motor and psychometric tests compared with the
previously achieved results. An increase of 5% was considered
Patients were divided into two groups. Those who
resulted positive in at least one of the invasive tests
underwent ventricular-peritoneal shunt implantation
(positive patients, PP); when both invasive tests were
negative, patients were denied the surgical procedure
(negative patients, NP).
All positive patients underwent ventricular-peritoneal
shunt implantation. The right ventricular frontal horn
was chosen for all patients and a Codman® Hakim®
programmable valve with pre-chamber was implanted. The
pressure of the valve was set with regards to the level
of clinical impairment, the neuroradiological images
and response to the invasive tests. Two days after
surgical intervention a head CT-scan was performed to
rule out surgical complications and to verify the
correct placement of the ventricular catheter. All patients
were discharged from hospital 5 to 7 days after
ventricular-peritoneal shunt implantation with a good
clinical recovery. One month after the ventricular peritoneal
shunt positioning, positive patients repeated the clinical
MRI was performed for each patient before and after
invasive tests and one month after ventricular peritoneal
shunt implantation (timing was chosen to permit good
recovery after the surgical procedure). For each patient,
perfusion and diffusion sequences were acquired and
values for relative cerebral blood flow (rCBF) and apparent
diffusion coefficient (ADC) were extrapolated.
Examinations were performed on a 3.0T
magnet (Achieva; Philips Medical Systems, Best, The
At the first MRI examination, all patients before
diffusion tensor imaging (DTI) and perfusion-weighted
imaging (PWI) studies, also underwent a standard brain
MRI protocol that included non-enhanced axial
inversion recovery (IR) T1-weighted images, sagittal 3D
T2-weighted images and axial fluid attenuated inversion
recovery (FLAIR) sequences. During the second and
third MRI examinations, only DTI and PWI sequences
Dynamic Susceptibility Contrast-Enhanced (DSC)
MR imaging was performed using gradient echo
planar T2*−weighted sequence with the following
parameters: TR = 1708 ms, TE = 40 ms, inplane
resolution = 1.75 × 1.75 mm, slice thickness = 4 mm, number
of slices = 25, slice GAP = 0 mm.
Ten seconds after the start of image acquisition, a
bolus of a 1.0 mmol/ml gadobutrol formula (Gadovist;
Schering Bayer Pharma, Leverkusen, Germany) in a
dose of 0.1 mmol/kg of body weight (as indicated by
the manufacturer) was injected via a 20-gauge catheter
placed in the antecubital vein. Contrast administration
was performed using an automatic injector (MEDRAD
Spectris Solaris EP MR injection System, Indianola PA,
USA) at a rate of 5 ml/s and was followed by a saline
bolus (20 ml at 5 ml/s). The dynamic images were
postprocessed using the vendor specific software on the
MRI scanner. For each patient, two different examiners,
one neurosurgeon and one neuroradiologist, placed
sixteen regions of interest (ROIs) in the same basal ganglia
region (i.e. nucleus caudatus, putamen, striatum) and in
PVWM area. Six ROIs were also positioned in cortical
occipital region. Careful positioning avoided inclusion
of other anatomical structures. During image
postprocessing the two examiners were blinded to patient
clinical evaluations and invasive test results, thus
ensuring that results were unbiased. As an example, Fig. 1
show ROIs positioned in the periventricular and basal
ganglia regions. For each ROI value the relative
cerebral blood flow (rCBF), relative cerebral blood volume
(rCMV) and mean transit time (MTT) were calculated.
In the present study, we used the rCBF as parameter of
choice, using the mean cortical occipital rCBF as
Diffusion-weighted images were acquired before
administration of contrast medium using a diffusion-weighted
single-shot echo-planar sequence with diffusion
gradients along the fifteen directions and effective b-values
of 0 and 1000 s/mm . ADC and fractional anisotropy
(FA) maps were automatically generated by the software
employed in the MRI scanner console. Scan
parameters of DTI sequence were as follows: TR = 7204 ms,
TE = 62 ms, inplane resolution = 1.62 × 1.62 mm,
slice thickness = 2 mm, number of slices = 60, slice
GAP = 0 mm.
ADC values were calculated in ROIs positioned in
basal ganglia and PVWM area and overlapped the
Descriptive analysis was performed: median,
interquartile range (IQR), mean and standard deviation
(SD) were calculated. The parameters of perfusion and
diffusion between PP versus NP groups and within
subjects were compared by Wilcoxon Mann–Whitney
test and Wilcoxon signed rank sum test, respectively.
For statistical analysis we applied relative perfusion
values, which were calculated using estimates for the
occipital cortex as an internal reference [
Differences in mean values of perfusion and diffusion from
baseline to post-surgery were estimated for each
patient. Spearman correlation was calculated. The
alpha level was set to 0.05 for all tests. The statistical
analysis was performed using Epi Info™ v. 3.5.1 and
Microsoft Excel software.
Thirteen patients (56.53%) had at least one positive result
in the invasive tests. We referred to this patient group as
positive patients (PP). Ten patients (43.47%) conversely
had no positive result either in the lumbar infusion test
or in the tap test. We referred to this patient group as
negative patients (NP).
In the PP group, six patients were male (46.15%)
and seven patients were female (53.85%); in the
NP group, four patients were male (40%), and six
patients were female (60%). For the PP the mean age
was 72.5 ± 6.94 years, whereas for NP mean age was
70.7 ± 6.78 years. Regarding invasive tests results in the
PP group 10 patients had a Rout greater than 13 mmHg/
min/ml (76.92%) and 10 patients had a positive result in
the tap test, showing a clinical improvement greater than
5% (Table 1). In the NP group no patient showed
clinical improvement after the tap test or a Rout greater than
13 mmHg/min/ml (Table 2).
Considering clinical characteristics, in the PP group,
clinical basal score ranged from 44.00 to 84.75 with an
average value of 61.54 ± 10.13. In the NP group, baseline
clinical score ranged from 22.50 to 78.25 with an average
value of 57.97 ± 16.51. No significant differences were
demonstrated between the two groups, either in total
clinical score or singular domain.
After invasive tests were performed, 10 patients of the
PP group showed clinical improvement with a clinical
score increase of more than 5%. Average improvement
rate was 26.45% ± 19.47% (Table 1). None of the NP
showed clinical improvement greater than 5% after the
Post-surgery % Variation
PP patients were clinically evaluated again 1 month
after ventriculo-peritoneal shunt implantation. In the
third clinical evaluation all PP patients showed
clinical improvement after shunt implantation. Average
improvement rate with respect to basal evaluation was
42.82% ± 17.15%. In Table 1 PP personal data, results
of invasive tests and clinical score at basal, post-test and
post-surgery evaluation are reported. In Table 2 the same
data for NP are summarized.
Perfusion and diffusion values of PP group are reported
in Table 3 for the periventricular and basal ganglia
regions. Values were obtained during the baseline
radiological study, after invasive test examination and after
shunt implantation. In Table 4 the same values are
summarized for the NP group.
Basal values of perfusion and diffusion between the
PP and NP groups were compared. No significant
differences were demonstrated at basal evaluation either in the
periventricular region, or in the basal ganglia region. The
post-invasive test values of perfusion and ADC were also
compared between the PP and NP groups and a
significant difference was found for perfusion values in both the
periventricular and the basal ganglia areas between two
patient groups. No significant differences were
demonstrated in either region for ADC values (Table 5).
Perfusion changes within the PP and NP groups were
analysed from basal to post-test and after surgery
procedure. A significant improvement of perfusion was
found in PP group both in BG region and PVWM area,
while NP group shows a significant decrease in the same
regions. In Figs. 2 and 3 periventricular and basal ganglia
perfusion variation from baseline evaluation to
post-surgery assessment in positive patients (PP) are represented.
When considering diffusion measurements within
each group, results are different. We found a significant
decrease of ADC values in PVWM area and a
significant increase in BG regions in PP group. In NP group
statistical significance was not reached either in PVWM
area or in BG. In Table 5 the median and IQR of
perfusion and diffusion of PP and NP groups and statistical
analysis are reported.
We also investigated the relationship between the
clinical score, ADC values, perfusion values and their variation
in PP group. Only the correlations that have an impact on
clinical and pathophysiological conditions are reported:
• Clinical score and periventricular ADC values in
basal and post-test evaluation: a significant inverse
correlation was demonstrated (rs = −0.51 and
rs = −0.56 respectively). In post-surgery evaluation
no significant correlation was detected (rs = −0.46).
• Periventricular perfusion and ADC variation from
basal to post-surgery evaluation: a significant inverse
correlation was reached (rs = −0.52).
• Spearman correlation of differential values of
perfusion and ADC in basal ganglia from basal to
post-surgery evaluation: a significant direct correlation was
reached (rs = 0.57).
Changes in cerebral blood perfusion in iNPH patients
compared with aged-matched controls, and changes
in brain tissue microstructure, have already been
demonstrated by multiple studies [
13, 14, 16–20, 24
this study we considered only patients with probable
iNPH. Patients were recruited over a limited period of
24 months and were prospectively followed; clinical and
radiological evaluations were made at the beginning,
after invasive tests and after shunt procedure. The patient
population was divided into two sub-groups: patients
who had at least one positive response to invasive tests
and who had undergone surgical treatment (PP group),
and patients who did not show any improvement after
the tap test or a significantly high Rout (NP group). After
A a n
Patients Perfusion mean values (rate)a
Periventricular white matter
Diffusion mean values (ADC mm2/s)b
Periventricular white matter
a Perfusion rates are expressed relative to that in the occipital cortex
b Diffusion is expressed using apparent diffusion coefficient (ADC) parameter
initial clinical data analysis, neither the total clinical score
nor the singular domain score showed significant
differences between the two groups of patients.
To evaluate cerebral perfusion we used a DSC MRI
perfusion sequence, a non-invasive technique. This
technique suffers from specific problems related to CBV and
CBF quantification in absolute terms. For inter-subject
comparison or follow-up evaluation relative perfusion
estimates are usually used. We chose occipital cortical
perfusion as the internal reference assuming that this
region would be less affected by global perfusion
19, 20, 30–32
The PVWM and BG perfusion data obtained at the
beginning of the study (basal values) are consistent with
values available in the literature for iNPH [
]. In the
baseline evaluation no significant differences were
demonstrated in perfusion values between PP and NP groups
either in PVWM region or in basal ganglia. Likewise no
significant difference was obtained in ADC values. Given
these results, the authors could not identify a radiological
perfusion or diffusion marker for selecting patients to
submit to surgery without carrying out invasive tests.
Perfusion values showed a different response between
the two groups after performing the invasive tests. In
the PP group, perfusion increased significantly both in
the periventricular and basal ganglia areas and the same
result was achieved after VP shunt. In the PP group we
detected clinical improvement in the majority of the
cases related to an increase of the CBF values after the
invasive tests were performed. These results is are
consistent with the ones in literature [
]. NP, on the other
hand, showed a significant decrease in perfusion values
after invasive tests both in PVWM and in basal ganglia
areas and no clinical improvement was achieved in these
patients. Significant differences were found for PVWM
and basal ganglia perfusion values between PP and NP
after performing the invasive tests.
Given the different perfusion patterns between PP
and NP, we suggest that perfusion MRI could be
useful together with invasive tests in selecting patients for
surgical treatment. As an example, three PP patients
(F) (N) (O) presented a Rout slightly above the
threshold value and no clinical improvement after tap test. All
these patients, however, showed a good improvement
in perfusion values in PVWM and BG. Patients were
subsequently submitted to surgery. A month after
VPshunt implantation these patients showed good clinical
improvement and CBF values increased even more. This
finding suggests that perfusion MRI (a non-invasive
technique) could enhance the selection of candidates for VP
In the PP group ADC values decrease significantly in
PVWM area due, in our opinion, to the interstitial edema
reduction after CSF drainage. However, in BG region a
significant increase in ADC values was observed. This
phenomenon could be related to relief of the chronic
hypoxic environment caused by hydrocephalus. In the
NP group no significant variation of ADC values was
observed. Correlating clinical and radiological data, the
authors found a significant inverse correlation between
clinical score and periventricular diffusion values in the
PP group in basal and post-test evaluations (i.e. patients
with higher diffusion values in PVWM area showed a
worse clinical score in the baseline exam). The authors
speculated that PVWM diffusion values are related to
trans-ependymal interstitial edema; this result is
consistent with the findings in literature [
19, 22, 33
Comparing perfusion and diffusion data from basal
to post-surgical evaluation, the authors found a
significant inverse correlation in PP group. For higher
diffusion values, we found lower CBF values. The authors
hypothesized that interstitial edema could reduce
microvascular blood flow and interfere with the blood
supply of these regions. After VP shunt implantation, more
CSF was drained; diffusion values decreased
(expression of reduced interstitial edema) and perfusion values
increased. Draining CSF acutely or chronically decreased
the interstitial edema present in PVWM areas in iNPH
patients, improving regional blood perfusion and
consequently achieving clinical improvement.
When considering the basal ganglia region, the
researchers found data that may describe a different
pathophysiological mechanism. A significant direct
correlation in the PP group between perfusion and
diffusion values from baseline to the postsurgical evaluation
was demonstrated. In previous studies, a chronic hypoxic
environment caused by hydrocephalus has been
17, 18, 20
]. Researchers considered that the
diffusion values calculated in basal ganglia areas could
be conditioned mainly by the chronic hypoxic
environment causing cytotoxic damage [
25, 26, 33
], as opposed
to what happens in the periventricular areas where the
mechanism underlying the chronic damage of the white
matter is mainly induced by the interstitial
After VP shunt implantation, perfusion improved
consistently in the basal ganglia; consequently the chronic
hypoxic insult decreased as the cytotoxic edema, and
diffusion values increase. We postulate that since
correlation is significant only when considering variation
from the baseline to postsurgical evaluation, a significant
amount of time (several weeks) is required to modify
the chronic hypoxic environment and improve cytotoxic
Moreover we argued that this different
pathophysiological mechanism between periventricular and basal
ganglia areas could be explained by the heterogeneity
of brain areas and different tissue structure: white
matter (with predominance of axons) in PVWM, grey matter
(with predominance of cellular bodies) in BG [
There are some underlying limitations of this study.
First of all, because of the limited number of patients
that influenced the statistical analysis; we were not able
to predict some important statistical measures such as
positive predictive value of perfusion MRI for selecting
patients as candidates for surgery. Another limitation is
related to the absence of data that could be derived from
negative patients after a hypothetical VP shunt
implantation (due to obvious ethical reasons). Those clinical
and radiological data could be relevant to confirm the
pathophysiological mechanisms we postulate and to
point out the role of perfusion and diffusion MRI in the
patient selection process.
This study (despite the limited number of patients)
allowed us to observe prospectively diffusion and
perfusion changes in probable iNPH patient candidates for
a VP shunt. Perfusion MRI (a non-invasive technique)
was found to be useful, together with invasive tests, for
selecting patients for surgery, increasing the specificity
in selected cases. Relationships between diffusion and
perfusion values estimated with MRI have been studied
and a hypothesis has been proposed to better clarify the
pathophysiological mechanisms in iNPH. Further studies
conducted on a wider patient population will be required
to validate the results observed in this prospective cohort
ADC: apparent diffusion coefficient; BG: basal ganglia; CSF: cerebral spinal
fluid; DTI: diffusion tensor imaging; FA: fractional anisotropy; FLAIR: fluid
attenuated inversion recovery; ICP: intracranial pressure; iNPH: idiopatic
normal pressure hydrocephalus; IR: inversion recovery; MRI: magnetic resonance
imaging; MTT: mean transit time; NP: negative patients; PP: positive patients;
PVWM: periventricular white matter; PWI: perfusion weighted imaging; rCBF:
relative cerebral blood flow; rCMV: relative cerebral blood volume; ROI: region
of interest; VP: ventricular-peritoneal.
All authors have contributed equally in the development of this clinical study.
All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
The datasets used and analysed during the current study are available from
the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was IRB approved and revised.
Consent for publication
No funding received from any Institution and/or Foundation.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Hakim S , Adams RD . The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. Observations on cerebrospinal fluid hydrodynamics . J Neurol Sci . 1965 ; 2 : 307 - 27 .
2. Relkin N , Marmarou A , Klinge P , Bergsneider M , Black PM . Diagnosing idiopathic normal-pressure hydrocephalus . Neurosurgery . 2005 ; 57 ( Suppl 3 ): S4 - 16 .
3. Cage TA , Auguste KI , Wrensch M , Wu YW , Gupta N. Self-reported functional outcome after surgical intervention in patients with idiopathic normal pressure hydrocephalus . J Clin Neurosci . 2011 ; 18 : 649 - 54 .
4. Eide PK , Sorteberg W. Diagnostic intracranial pressure monitoring and surgical management in idiopathic normal pressure hydrocephalus: a 6-year review of 214 patients . Neurosurgery. 2010 ; 66 : 80 - 91 .
5. Hashimoto M , Ishikawa M , Mori E , Kuwana N. Diagnosis of idiopathic normal pressure hydrocephalus is supported by MRI-based scheme: a prospective cohort study . Cerebrospinal Fluid Res . 2010 ; 7 : 18 .
6. Klinge P , Hellström P , Tans J , Wikkelsø C , on behalf of the European iNPH Multicentre Study Group . One-year outcome in the European multicenter study on iNPH . Acta Neurol Scand . 2012 ; 126 : 145 - 53 .
7. Lemcke J , Meier U . Improved outcome in shunted iNPH with a combination of a Codman Hakim programmable valve and an Aesculap-Miethke Shunt Assistant . Cent Eur Neurosurg . 2010 ; 71 : 113 - 6 .
8. Katzman R , Hussey F. A simple constant-infusion manometric test for measurement of CSF absorption I. rationale and method . Neurology . 1970 ; 20 : 534 - 44 .
9. Eklund A , Smielewski P , Chambers I , et al. Assessment of cerebrospinal fluid outflow resistance . Med Biol Eng Comput . 2007 ; 45 : 719 - 35 .
10. Tans JT , Poortvliet DC . CSF outflow resistance and pressure-volume index determined by steady-state and bolus infusions . Clin Neurol Neurosurg . 1985 ; 87 : 159 - 65 .
11. Wikkelsø C , Hellström P , Klinge P , Tans J , on behalf of the European iNPH Multicentre Study Group. The European iNPH Multicentre Study on the predictive values of resistance to CSF outflow and the CSF Tap Test in patients with idiopathic normal pressure hydrocephalus . J Neurol Neurosurg Psychiatry . 2013 ; 84 ( 5 ): 562 - 8 .
12. Marmarou A , Bergsneider M , Klinge P , Relkin N , Black PM . The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal pressure hydrocephalus . Neurosurgery . 2005 ; 57 ( 3 Suppl) : S17 - 28 .
13. Owler BK , Pickard JD . Normal pressure hydrocephalus and cerebral blood flow: a review . Acta Neurol Scand . 2001 ; 104 : 325 - 42 .
14. Owler BK , Momjian S , Czosnyka Z , et al. Normal pressure hydrocephalus and cerebral blood flow: a PET study of baseline values . J Cereb Blood Flow Metab . 2004 ; 24 : 17 - 23 .
15. Owler BK , Pena A , Momjian S , et al. Changes in cerebral blood flow during cerebrospinal fluid pressure manipulation in patients with normal pressure hydrocephalus: a methodological study . J Cereb Blood Flow Metab . 2004 ; 24 : 579 - 87 .
16. Momjian S , Owler BK , Czosnyka Z , Czosnyka M , Pena A , Pickard JD . Pattern of white matter regional cerebral blood flow and autoregulation in normal pressure hydrocephalus . Brain . 2004 ; 127 : 965 - 72 .
17. Klinge PM , Samii A , Muhlendyck A , et al. Cerebral hypoperfusion and delayed hippocampal response after induction of adult kaolin hydrocephalus . Stroke . 2003 ; 34 : 193 - 9 .
18. Luciano MG , Skarupa DJ , Booth AM , Wood AS , Brant CL , Gdowski MJ . Cerebrovascular adaptation in chronic hydrocephalus . J Cereb Blood Flow Metab . 2001 ; 21 : 285 - 94 .
19. Calamante F. Perfusion MRI using dynamic-susceptibility contrast MRI: quantification issues in patient studies . Top Magn Reson Imaging . 2010 ; 21 ( 2 ): 75 - 85 .
20. Ziegelitz D , Starck G , Kristiansen D , et al. Cerebral perfusion measured by dynamic susceptibility contrast MRI is reduced in patients with idiopathic normal pressure hydrocephalus . J Magn Reson Imaging . 2014 ; 39 ( 6 ): 1533 - 42 .
21. Aygok G , Marmarou A , Fatouros P , Young H . Brain tissue water content in patients with idiopathic normal pressure hydrocephalus . Acta Neurochir Suppl . 2006 ; 96 : 348 - 51 .
22. Demura K , Mase M , Miyati T , et al. Changes of fractional anisotropy and apparent diffusion coefficient in patients with idiopathic normal pressure hydrocephalus . Acta Neurochir Suppl . 2012 ; 113 : 29 - 32 .
23. Ng SE , Low AM , Tang KK , Lim WE , Kwok RK . Idiopathic normal pressure hydrocephalus: correlating magnetic resonance imaging biomarkers with clinical response . Ann Acad Med Singap . 2009 ; 38 ( 9 ): 803 - 8 .
24. Corkill RG , Garnett MR , Blamire AM , Rajagopalan B , Cadoux-Hudson TA , Styles P. Multi-modal MRI in normal pressure hydrocephalus identifies pre-operative haemodynamic and diffusion coefficient changes in normal appearing white matter correlating with surgical outcome . Clin Neurol Neurosurg . 2003 ; 105 ( 3 ): 193 - 202 .
25. Shevtsov MA , Senkevich KA , Kim AV , et al. Changes of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the model of experimental acute hydrocephalus in rabbits . Acta Neurochir (Wien) . 2015 ; 157 ( 4 ): 689 - 98 .
26. Chu BC , Miyasaka K. The clinical application of diffusion weighted magnetic resonance imaging to acute cerebrovascular disorders . No To Shinkei. 1998 ; 50 ( 9 ): 787 - 95 .
27. Hellstrom P , Klinge P , Tans J , Wikkelso C. A new scale for assessment of severity and outcome in iNPH . Acta Neurol Scand . 2012 ; 126 : 229 - 37 .
28. Boon AJ , Tans JT , Delwel EJ , et al. Dutch normal-pressure hydrocephalus study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid . J Neurosurg . 1997 ; 87 ( 5 ): 687 - 93 .
29. Børgesen SE , Albeck MJ , Gjerris F , Czosnyka M , Laniewski P . Computerized infusion test compared to steady pressure constant infusion test in measurement of resistance to CSF outflow . Acta Neurochir (Wien) . 1992 ; 119 ( 1-4 ): 12 - 6 .
30. Meyer JS , Kitagawa Y , Tanahashi N , et al. Pathogenesis of normal-pressure hydrocephalus-preliminary observations . Surg Neurol . 1985 ; 23 : 121 - 33 .
31. Vorstrup S , Christensen J , Gjerris F , Sorensen PS , Thomsen AM , Paulson OB . Cerebral blood flow in patients with normal-pressure hydrocephalus before and after shunting . J Neurosurg . 1987 ; 66 : 379 - 87 .
32. Ziegelitz D , Arvidsson J , Hellström P , Tullberg M , Wikkelsø C , Starck G. In patients with idiopathic normal pressure hydrocephalus postoperative cerebral perfusion changes measured by dynamic susceptibility contrast magnetic resonance imaging correlate with clinical improvement . J Comput Assist Tomogr . 2015 ; 39 : 531 - 40 .
33. Mascalchi M , Filippi M , Floris R , Fonda C , Gasparotti R , Villari N. Diffusionweighted MR of the brain: methodology and clinical application . Radiol Med . 2005 ; 109 ( 3 ): 155 - 97 .