Acta Neurol Scand 2007: 116: 328–332 DOI: 10.1111/j.1600-0404.2007.00906.
x Copyright  2007 The Authors
Caudate structural abnormalities in
idiopathic normal pressure hydrocephalus
DeVito EE, Salmond CH, Owler BK, Sahakian BJ, Pickard JD.
Caudate structural abnormalities in idiopathic normal pressure
hydrocephalus.
Acta Neurol Scand 2007: 116: 328–332.
 2007 The Authors Journal compilation  2007 Blackwell Munksgaard.
Background – Idiopathic normal pressure hydrocephalus (iNPH) is a
reversible dementia in which fronto-striatal cognitive deficits and
apathy may be present. Objectives – The study investigated structural
volumetric changes in iNPH, apart from ventriculomegaly. Materials
and methods – A full-brain voxel-based morphometric analysis
between 11 iNPH patients and 14 healthy controls identified regions
of interest (ROIs) for manual volumetric analyses. Results – Caudate
and corpus callosum ROI measurements revealed diminished caudate
nuclei volume in the iNPH group. Conclusions – The role of the
caudate nucleus in cognitive and affective changes in iNPH should
now be explored.
Introduction
Normal pressure hydrocephalus (NPH) is a revers-
ible dementia: cerebrospinal fluid (CSF) diversion
may alleviate its key features of gait disturbance,
dementia and urinary incontinence (1). Previous
studies investigated sulcal atrophy (2), white
matter lesions (3) and CSF flow (4) as diagnostic
or prognostic markers. However, brain-wide inves-
tigations of NPH morphology have not been
conducted.
Several structural changes observed in NPH
have been proposed to contribute to the symptom
triad. Hippocampal atrophy has been demon-
strated in some patients (5), yet it may be explained
in part by co-morbid AlzheimerÕs disease (6).
Jinkins (7) suggested impingement of the corpus
callosum caused NPH symptoms, but the finding
has not generalized to all patient samples (8). The
degree of preoperative ventriculomegaly does not
predict the shunt response (9), and change in
ventricular volumes does not correlate with symp-
tom improvement following shunt (10). However,
328
Journal compilation  2007 Blackwell Munksgaard
ACTA NEUROLOGICA
SCANDINAVICA
E. E. DeVito1,2, C. H. Salmond1,3,
B. K. Owler2,4, B. J. Sahakian1,
J. D. Pickard2,3
1
Department of Psychiatry, School of Clinical Medicine,
University of Cambridge, Cambridge, UK; 2Division of
Neurosurgery, Department of Clinical Neurosciences,
School of Clinical Medicine, University of Cambridge,
Cambridge, UK; 3Wolfson Brain Imaging Centre,
University of Cambridge, Cambridge, UK; 4Department
of Neurosurgery, Westmead Hospital, Wentworthville,
NSW, Australia
Key words: caudate; corpus callosum; fronto-striatal
dementia; normal pressure hydrocephalus
John D. Pickard, Division of Neurosurgery, Adden-
brookeÕs Hospital, Box 167, Cambridge CB2 2QQ, UK
Tel.: +44 01223 336929
Fax: +44 01223 216926
e-mail: prof.jdp@medschl.cam.ac.uk
Accepted for publication June 26, 2007
associated periventricular white matter disruption
has been repeatedly demonstrated and widely
hypothesized to contribute to symptoms and
prognosis (e.g. 11).
Some NPH symptoms may have a subcortical
origin. Subcortical pathology often causes gait
disturbances and fronto-striatal cognitive impair-
ments (12), consistent with the pattern of decline in
NPH (13). We have previously demonstrated using
positron emission tomography (PET) that there are
pronounced reductions in basal ganglia and peri-
ventricular regional cerebral blood flow (rCBF),
which correlate in the putamen with gait dysfunc-
tion and in the thalamus with global symptom
ratings (modified Stein–Langfitt) (14).
The aim of the present study was to use voxel-
based morphometry (VBM) to perform a brain-
wide search for structural changes in idiopathic
normal pressure hydrocephalus (iNPH) (vs a con-
trol group) to identify regions of interest (ROIs) for
volumetric analyses. Based on the symptoms and
known neuropathology in NPH, we predicted that
we would find reduced basal ganglia volume.
 Abnormal caudate in iNPH

time (TR) 9.7 ms, echo time (TE) 4 ms, inversion

Materials and methods
Patient and control scans were collected with the
approval of The Cambridge Local Research Ethics
Committee (03 ⁄ 141; 01 ⁄ 089), in accordance with
the Declaration of Helsinki.
Selection of volunteers
Eleven iNPH patients were diagnosed through the
AddenbrookeÕs Hospital CSF Clinic as having the
typical clinical and neuropsychological profile,
ventriculomegaly on magnetic resonance scans,
and in nine cases raised CSF outflow resistance
(15). Patients were free of co-morbid psychiatric or
neurological disorders and were scanned success-
fully prior to CSF diversion. All eleven patients
improved following insertion of a programmable
ventriculoperitoneal shunt (see Table 1).
Fourteen healthy controls were recruited from
the local community using posters and then
prescreened in a telephone interview to exclude
for history of psychiatric or neurological disorders,
drug or alcohol abuse, head injury, medicated
hypertension or diabetes. ParticipantsÕ scans were
reviewed by a radiologist and excluded from the
analysis for any reported abnormalities other than
moderate periventricular hyperintensities (n = 4),
which are prevalent in normal elderly populations
(16).
Magnetic resonance imaging (MRI) data acquisition
Participants were scanned on a 3.0 T Bruker Med-
spec S300 (Bruker Medical, Ettlingen, Germany)
using a T1-weighted 3D spoiled gradient recalled
echo (SPGR) sequence with parameters: repetition
Table 1 Patient clinical profiles and responses to ventriculoperitoneal shunt
time (TI) 300 ms, flip angle 12, matrix size
256 · 256 · 128, field of view 250 · 250 · 160 mm.
VBM determination of ROIs
Voxel-based morphometry quantifies regional
tissue differences with whole-brain sensitivity.
Scans were reorientated to the anterior–posterior
commissure line, spatially normalized with
12-parameter affine transformation (17) to the
standard Montreal Neurological Institute T1 tem-
plate and smoothed with 12-mm isotropic Gauss-
ian kernels. Affine normalization was applied
independently of non-linear techniques to avoid
promoting localized expansion or contraction of
structures (18).
Ventriculomegaly prevented reliable segmenta-
tion using local group or spm2 templates (Wellcome
Department of Imaging Neuroscience, London,
UK). While standard VBM preprocessing includes
segmentation, unsegmented scans are analysed in
spm for diffusion tensor imaging studies (19). VBM
without segmentation cannot specify changes in
grey or white matter density. Instead, Ôregional
tissue signal intensityÕ group differences could
reflect pathology, variations in tissue type distri-
bution or volumetric changes.
Unsegmented scans were analysed in spm2 with
matlab 6 (Mathworks, Natick, MA, USA). Single
contrasts were tested for decreased or increased
regional tissue signal intensity in iNPH vs controls.
VBM results were adjusted for multiple compari-
sons using family-wise error (FWE) correction (20).
To conservatively account for any data artefacts
insufficient normalization may produce, VBM was
used to identify ROIs. VBM group differences not
confirmed by separate ROI volumetric analyses
were interpreted cautiously.

Preshunt infu-
sion study Response to shunt ROI guidelines

Age Sex OP rCSF Gait Cognition Continence Regions of interest were measured in analyze
(Mayo Foundation, Rochester, MI, USA) on raw
63 F 6 11 › ⁄ –
MRI data oriented by an investigator blinded to
66 F 12 19 › › ›
69 F 12 27 › › › diagnosis, sex and age. ROIs consisted of caudate
71 F 11 10 › › › nuclei and corpus callosum, as determined by
72 M 16 32 › › › VBM; ventricles, due to established ventriculomeg-
73 F 12 22 › › › aly (1); and cranial vault, to correct for variability
74 M 9 15 › › ›
74 M 14 27 › – ›
in head size (21).
78 F 16 19 › › ⁄ Caudate head and body were measured with the
78 M 11.5 20 › › › manual Trace function on contiguous axial slices
81 M 10 19 › – › and delineated by the anterior limb of the internal
Preshunt measures: OP, opening pressure (mmHg); rCSF, resistance to CSF outflow
capsule, lateral ventricles and inferiorly by the
(mmHg ⁄ ml ⁄ min). Post-shunt response: (›) improvement; (–) no improvement; ( ⁄ ) anterior commissure (22). Semi-automated Auto-
no initial deficit. trace function measured corpus callosum area at the

329
DeVito et al.

midline sagittal slice (23). The manual Splice func- Table 2 ROI volumetric differences
tion measured cranial vault every 10 sagittal slices
Structure iNPH group Control group d.f. (total) F P-value
(24) along the inner skull border; lateral ventricles
every five slices; third and fourth ventricles on Left caudate 2.9  0.4 3.3  0.4 1 (25) 5.18 0.033*
contiguous slices. Multiplying by slice thickness and Right caudate 2.7  0.4 3.4  0.4 1 (25) 16.14 0.001*
interval converted the data to volumes. Corpus callosum 5.6  1.9 1.1  0.3 1 (25) 4.09 0.055
Lateral ventricles 193.8  82.6 30.4  14.8 1 (25) 50.65 <0.001*
Intra-rater reliability was assessed using two Third ventricle 6.0  3.1 1.8  0.6 1 (25) 21.75 <0.001*
methods. Five subjects (two iNPH; three controls) Fourth ventricle 2.5  1.2 1.2  0.4 1 (25) 12.47 0.002*
were randomly chosen for retracing of all struc- Cranial vault 2130.9  133.4 2064.8  244.2 1 (25) 0.65 0.43
tures on axial slices as described above. Further-
Values represent mean  SD and are reported in cm3 except corpus callosum
more, caudate nuclei were retraced on all scans in (cm2). Statistics (F, P-value) were calculated with separate analyses of covariance,
coronal orientation, using lateral ventricles and corrected for cranial vault volumes. *Significance at the 0.05 level (two-tailed).
internal capsules as borders. ROI, regions of interest; iNPH, idiopathic normal pressure hydrocephalus.

ROI statistical analysis

LeveneÕs test of variances and independent sample
t-tests in spss (SPSS Inc., Chicago, IL, USA) 11.0
compared iNPH and control groups on age and sex.
Intra-class correlations (a) calculated intra-rater
reliability. Shapiro–WilkeÕs W tested normality of
ROI data. Univariate ANCOVAs, co-varied for
cranial vault volume, measured group differences
for each structure (25). ANOVA tested cranial
vault group differences.
A secondary question arose as to whether there
were associations between caudate and lateral or
third ventricle volumes, or between corpus callo-
sum and lateral ventricle volumes. These explor-
atory analyses were performed using within-group
Bonferroni-corrected correlations.
(x = )20, y = )36, z = 34), PFWEcorr < 0.001
and left head of caudate: (x = )12, y = 8,
z = 12), PFWEcorr = 0.002.
Retracing reliability was satisfactory for all
structures on axial scans (a = 0.93–0.99) and the
caudate across axial and coronal orientations (left,
a = 0.85; right, a = 0.93). The iNPH group had
reduced bilateral caudate volume, increased ven-
tricular volumes and a trend towards decreased
corpus callosum midsagittal area, with no differ-
ence in cranial vault volume (see Table 2).
A secondary question as to whether there were
associations between ROI volumes was examined.
None of the post hoc correlations between ROIs
remained significant following correction for multi-
ple comparisons.

Results
Controls did not significantly differ in age (mean
69; range 57–83) or sex (six men; eight women)
from iNPH (mean age 73, P = 0.167; range 63–81,
P = 0.376; five men, six women, P = 0.902).
Voxel-based morphometry revealed decreased
signal intensity in iNPH left and right caudate and
corpus callosum regions, identifying those struc-
tures for ROI analysis (see Fig. 1). Voxels with peak
statistical significance were in the corpus callosum:
Discussion
To our knowledge, this is the first demonstration of
diminished caudate volumes in iNPH. In addition,
a trend towards reduction in the midsagittal area of
the corpus callosum was found.
This study design capitalized on complementary
approaches of full-brain VBM and well-established
ROI analyses. Although all attempts were made to
blind the investigator to diagnosis whilst measuring
ROIs, ventriculomegaly was noticeable on iNPH

Figure 1. VBM identification of ROIs. Regions of decreased signal intensity (red) in iNPH versus control scans are corrected to
PFWE <0.05 and imposed on a mean of all scans.

330

and some control scans. However, VBM provided
a standardized independent measure, and the
reliability of repeated measures suggests that ROI
guidelines were applied consistently. The sample
size was limited by strict inclusion criteria, ensuring
accurate diagnosis. Idiopathic NPH patients were
chosen to avoid co-morbidities associated with
independent structural changes.
The ROI results, observed with 3D SPGR,
indicate tissue loss, but the cause remains unclear.
Corpus callosum abnormalities like bowing, thin-
ning, lengthening and occasional impingement are
well described in hydrocephalus and have been
suggested to reflect morphological distortion as
well as adjacent white matter disease (8). However,
the reduction in volume of the caudate nuclei and
corpus callosum were not related to the degree of
ventriculomegaly.
Healthy caudate functional activity correlates
with verbal memory (25), executive function (26)
and psychomotor speed (27). These cognitive
functions are often disrupted in NPH (13). Apa-
thetic behaviour, a symptom of NPH (28), is
commonly associated with caudate infarcts (29).
Cognitive decline in NPH may relate to reduced
caudate tissue volume and rCBF (14), but a much
larger population of patients will be required to
examine both this issue and the relationship to gait
dysfunction.
As iNPH symptoms are reversible in many cases
following CSF diversion, how does this relate to
caudate volume loss? Brain deformation results in
shear and compressive stress that can cause focal
cerebral hypoperfusion sufficient to produce clin-
ical symptoms which are reversible with treatment
of the deformation (30).
In summary, to our knowledge, this is the first
demonstration of diminished caudate nuclear
tissue volume in iNPH. Future studies should
clarify whether cognitive and behavioural NPH
symptoms and their response to CSF diversion are
predicted by caudate abnormalities.
Acknowledgements
We thank the WBIC radiographers and Prof. LT TylerÕs
laboratory for their contributions. This research was funded by
the Medical Research Council (G9439390 ID56883) and
Merck, Sharp & Dohme. Elise DeVito holds a Pinsent-
Darwin Research Studentship.
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