FN n. 3-2016 interno_.
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Spectrum of cognitive disorders in idiopathic
normal pressure hydrocephalus
Marta Picascia, PsyDa,b
Brigida Minafra, MDa
Roberta Zangaglia, MDa
Luciana Gracardia
Nicolò Gabriele Pozzi, MDa
Elena Sinforiani, MDb
Claudio Pacchetti, MDa
a
Parkinson’s Disease and Movement Disorders Unit,
C. Mondino National Neurological Institute, Pavia,
Italy
b
Alzheimer’s Disease Assessment Unit/Laboratory of
Neuropsychology, C. Mondino National Neurological
Institute, Pavia, Italy
Correspondence to: Marta Picascia
E-mail: marta_picascia@yahoo.it
Summary
Idiopathic normal pressure hydrocephalus (iNPH)
is a syndrome characterized by ventricular dilation
accompanied by a progressive triad of a gait distur-
bance, “dementia” and incontinence. We retrospec-
tively evaluated cognitive profile, and its relation-
ship with disease variables, in 64 iNPH patients.
The iNPH group performed significantly worse than
the control group on all neuropsychological tests,
except for verbal memory (within the normal range).
The patients were subdivided into four groups:
group 1 (42%: global cognitive impairment); group
2 (24%: frontosubcortical dysfunction); group 3
(17%: isolated deficit of a single cognitive domain);
group 4 (17%: no cognitive impairment). Group 1
was older, with a significantly longer disease dura-
tion and more severe motor disease, while groups
3 and 4 were younger and presented milder motor
impairment and a shorter disease duration. These
data suggest parallel progression of cognitive and
motor impairment in iNPH; early shunt surgery
might prevent the development, in older age, of
dementia in these patients.
KEY WORDS: cognitive disorders, disease duration, gait distur-
bances, idiopathic normal pressure hydrocephalus, parkinsonism
Functional Neurology 2016; 31(3): 143-147
Introduction
Idiopathic normal pressure hydrocephalus (iNPH) is a
complex syndrome first described by Adams et al.
(1965) as ventricular dilation accompanied by a pro-
gressive triad of a gait disturbance, “dementia” and
incontinence. Gait and balance disorders are the main
clinical presentations, whereas cognitive decline
appears as the disease progresses (Williams and
Relkin, 2013).
The incidence of iNPH is between 2 and 6% among
people affected by any dementia condition; it is con-
sidered an infrequent disease, but its occurrence is
probably underestimated because of diagnostic chal-
lenges. Recent epidemiological studies report an
increasing prevalence with increasing age, without dif-
ference between men and women, and confirm that
this pathology is underdiagnosed (Jaraj et al., 2014;
Martin-Láez et al., 2015).
Guidelines and operating criteria for the diagnosis and
management of iNPH have been proposed (Marmarou
et al., 2005; Ishikawa et al., 2008; Mori et al., 2012,
Williams and Relkin, 2013). The latter authors, in their
detailed indications, stress the concept that the start-
ing point should be a comprehensive history and neu-
rological examination, review of neuroimaging, and
evaluation of the differential diagnosis (Williams and
Relkin, 2013).
The cognitive and behavioral disturbances accompa-
nying iNPH have commonly been described as “fron-
tosubcortical dysfunction” (Ogino et al., 2006; Tarnaris
et al., 2011; Williams and Relkin, 2013). This clinical
term is used to refer to a pattern of mental decline
characterized by executive dysfunction, psychomotor
slowing and mood symptoms, especially apathy.
However, as reported in a recent review by Picascia et
al. (2015), this definition is reductive, because it does
not encompass the entire clinical spectrum. Patients
with iNPH actually present impairment in broader cog-
nitive domains: attention, working memory, episodic
memory, visuoperceptual and visuospatial functions
(Iddon et al., 1999; Walchenbach et al., 2002, Saito et
al., 2011; Bugalho et al., 2014); some studies in par-
ticular have focused on posterior cortical functions,
such as visuoperceptual and visuospatial functions.
The relationships between cognitive symptoms and
other clinical variables in iNPH have not been complete-
ly defined; some authors found a positive correlation
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M. Picascia et al.
with motor disturbances (Golomb et al., 2000), while
others failed to confirm this (Bugalho et al., 2014).
In the present study we retrospectively evaluated cog-
nitive profile, and its relationship with disease vari-
ables, in a group of subjects with iNPH.
Materials and methods
Materials
We retrospectively studied clinical charts collected from
January 2010 to December 2014, at the Parkinson’s
Disease and Movement Disorders Unit of the C.
Mondino National Neurological Institute in Pavia, Italy. A
case series of 64 subjects with a diagnosis of “probable”
iNPH was collected. All the recruited patients had been
referred to our unit with primary diagnoses of “parkin-
sonism”.
The diagnosis of iNPH was made on the basis of clini-
cal, neuropsychological and neuroimaging features
(Williams and Relkin, 2013). The main neuroimaging
features were ventricular enlargement not entirely attrib-
utable to cerebral atrophy or congenital enlargement
(Evans index > 0.3) and no macroscopic obstruction to
CSF flow, and they had to be accompanied by at least
one of the following supportive features: enlargement of
the temporal horns of the lateral ventricles not entirely
attributable to hippocampal atrophy; narrowing of the
sulci and subarachnoid spaces over the high convexi-
ty/midline surface; a callosal angle of 40° or more; evi-
dence of altered brain water content, including periven-
tricular signal changes on CT and MRI not attributable to
microvascular ischemic changes or demyelination; an
aqueductal or fourth ventricular flow void on MRI.
All the patients had a positive spinal tap.
Evidence of a relevant antecedent event such as head
trauma, intracerebral hemorrhage, meningitis, or other
known causes of secondary hydrocephalus were
excluded as were other neurological, psychiatric, or
general medical conditions capable of explaining the
symptoms.
Fifty-eight healthy elderly people, matched for age, sex
and education, served as normal controls (NCs); these
subjects were drawn from our historical archive of NCs
recruited among hospitalized patients and/or patients’
relatives without neurological disorder or cognitive
impairment.
All the patients and NCs were examined by a neurolo-
gist and tested by a neuropsychologist.
Methods
Evaluation of motor symptoms
Motor symptoms were evaluated using the Unified
Parkinson’s Disease Rating Scale Part III (UPDRS III);
this is a clinician-administered scale that is currently
applied to measure the motor impairment due to parkin-
sonism (Goetz et al., 2008; Antonini et al., 2013).
144
Neuropsychological assessment
The following neuropsychological tests were adminis-
tered to evaluate various cognitive domains:
- Mini-Mental State Examination – MMSE (Folstein et
al., 1975): general index of cognitive functioning
- Digit Span forward, Word Span and Spatial Span –
Corsi tests (Spinnler and Tognoni, 1987): working mem-
ory
- Rey’s 15-word test (Carlesimo et al., 1996), both
immediate and delayed recall: long-term verbal memory
- Logical memory test (Spinnler and Tognoni, 1987):
long-term verbal memory for structured material
- Raven’s Colored Matrices 47 (Carlesimo et al., 1996):
visuospatial reasoning
- Weigl’s Sorting Test (Spinnler and Tognoni, 1987): cat-
egorical abstract thinking
- Frontal Assessment Battery – FAB (Apollonio et al.,
2005): fronto-executive functioning
- Attentive matrices (Spinnler and Tognoni, 1987): selec-
tive attention
- Tests of phonological and semantic fluency (Carle-
simo et al., 1996; Spinnler and Tognoni, 1987): lexical
store
- Constructive Apraxia (Spinnler and Tognoni, 1987):
copying and visuospatial abilities.
Age-, gender- and education-corrected scores were cal-
culated from the raw scores; the corrected scores were
then transformed into equivalent scores, ranging from 0
(pathological) to 1 (lower limit of normal) and 2, 3, 4
(normal).
Statistical analysis
Statistical analysis was performed using the Statistical
Package for the Social Sciences, version 17.0 for
Windows (SPSS Inc., Chicago, IL).
Quantitative variables were described as means ± stan-
dard deviations (M±SD) and qualitative data as numbers
and percentages. One-way analysis of variance
(ANOVA) was used to detect significant differences
between iNPH patients and HCs and between the differ-
ent subgroups. Comparisons of percentages were per-
formed using the chi-square test.
For all analyses, the level of statistical significance was
set at p<0.05.
Results
As reported in table I, in comparison with the NCs, the
iNPH patients performed worse on almost all the neu-
ropsychological tests, except for Rey’s 15-word test,
immediate recall, and the Logical memory test, which
were within the normal range.
Taking into account the different cognitive domains
involved, and on the basis of equivalent scores, it
emerged that the entire iNPH population could be sub-
divided into the following groups:
- group 1 (G1): 27 patients (42%) with global cognitive
impairment, characterized by global deficit of cognitive
Functional Neurology 2016; 31(3): 143-147
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Spectrum of cognitive disorders in idiopathic normal pressure hydrocephalus

functions, or in any case by diffuse cognitive impair-

profiles: comparisons between iNPH patients and
The G1 patients, compared with the other groups, were
n
ment; older, with a significantly longer disease duration and
- group 2 (G2): 15 patients (24%) with the more typical more severe motor impairment (p<0.00001). UPDRS III
deficits in attention and executive abilities (frontosubcor- total score showed significant differences between G2
tical dysfunction); versus G3 and G4 patients (p<0.02 and p<0.0001,
- group 3 (G3): 11 patients (17%) with mild cognitive respectively). No differences were found between G3
impairment, i.e. involving a single domain (isolated and G4.
deficit of a single cognitive domain, e.g. memory, atten-
tion, visuospatial abilities);
- group 4 (G4): 11 patients (17%) with no cognitive Discussion
impairment.
The clinical, demographic and motor characteristics of profiles:
The results ofcomparisons
this study show between iNPH with
that, in comparison patients and
n different groups are reported in table II.
the the controls, our entire iNPH population was impaired

Table I - Demographic and neuropsychological profiles: comparisons between iNPH patients and normal controls.

Test/subtest iNPH NCs p-value

Subjects, F/M 64, 29–35 58, 26–32
Age (years) 73.7±7.5 (range 66–81) 76.0±5.8 (range 71–81) ns
Education (years) 8±5 8±5 ns
Disease duration (months) 40.1±31.8 (range 8–71)
MMSE 21.8±4.9 28.5±1.5 0.000000001
Digit span forward 4.4±0.7 5.1±1.3 0.0008
Word span 3.8±0.7 4.2±0.9 0.01
Spatial span (Corsi) 3.4±1.0 5.0±1.3 0.00000002
Rey’s 15-word test
-! Immediate recall 31.2±7.5 33.1±2.4 ns
-! Delayed recall 4.7±3.6 7.1±2.3 0.0001

Logical Memory test 6.9±4.3 8.2±3.4 ns

!
Raven’s Colored Matrices 47 21.0±6.6 25.1±5.3 0.0007
Weigl’s Sorting Test 5.9±2.9 7.2±2.1 0.01
Frontal Assessment Battery (FAB) 11.5±3.6 15.6±1.8 0.00000008
Attentive matrices 34.8±12.1 42±6.9 0.0003
Verbal fluency:
-! Phonological 19.9±9.2 23.1±4.3 0.02
-! Semantic 12.1±3.4 14.0±2.6 0.002

Constructive Apraxia 10.9±2.6 12.1±1.9 0.009

Abbreviations: iNPH=idiopathic normal pressure hydrocephalus; NCs=normal controls; F/M=females/males; ns=not significant. Between-group differences
were assessed with one-way ANOVA; values are expressed as means±SD.
!

Table II - Demographic and clinical characteristics of the different iNPH groups.

G1 G2 G3 G4
Global cognitive Frontosubcortical MCI single domain No cognitive
impairment dysfunction impairment
(27 pts) (15 pts) (11 pts) (11pts)
Sex M/F 13/14 10/5 7/4 5/6
Age (years) 79.3±1.9* 73.7±7.5 70.4±4.2 69.9±3.2
Disease duration 54.2±16.8* 40.0±31.0 33.3±13.2 32.4±11.3
(months)
UPDRS III 36.6±10.0* 26.3±3.1°+ 20.6±8.4 21.4±2.3
range 47–27 range 29–22 range 29–10 range 24–16

Abbreviations: G=Group; MCI=mild cognitive impairment; UPDRS III=Unified Parkinson’s Disease Rating Scale Part III. *=G1 vs G2, G3 and G4:
p<0.00001; °=G2 vs G3: p<0.02; +=G2 vs G4: p<0.0001.Between-group differences were assessed with one-way ANOVA; values are expressed as
means±SD.

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M. Picascia et al.
in almost all neuropsychological measures; the extent
of the statistical significance of the differences varied
from test to test, being more pronounced in tests eval-
uating logical and executive functions. Only episodic
memory was relatively preserved; these data seem to
suggest that memory impairment in iNPH is generally
milder compared with the impairment of other func-
tions, executive ones in particular (Ogino et al., 2006).
However, when we considered the different cognitive
domains involved, we were able to identify subgroups
of patients with different cognitive profiles: about half
of the subjects (42%) presented a global-diffuse
impairment which can be framed as dementia of mild
to moderate degree. Among the patients classified as
non-demented, only 24% presented frontosubcortical
dysfunction; we also found a subgroup with impair-
ment in a single cognitive domain, and even patients
without any neuropsychological deficit.
Therefore, our results are in agreement with literature
data documenting a wide range of cognitive pictures in
iNPH (Iddon et al., 1999; Walchenbach et al., 2002;
Saito et al., 2011; Bugalho et al., 2014; Picascia et al.,
2015); in particular, the definition “frontosubcortical
dysfunction” is reductive as it does not encompass the
entire spectrum of different cognitive profiles.
The second important finding of our study was the
positive correlation detected between cognition and
disease progression; in fact, although cognitive
impairment may be absent in younger patients, it
undoubtedly becomes more severe with older age,
increasing disease duration and increasing severity of
motor disturbances. This correlation points to the pos-
sible existence of a common pathophysiological
mechanism. From this perspective, our data seem to
suggest that early shunt surgery might be a way of
limiting not only the progression of motor disturbances
but also the advance of cognitive impairment in these
patients.
Our sample was enrolled on the basis of the presence
of gait disturbances/parkinsonism; this was indeed the
reason they were referred to our unit. This aspect may
represent a weakness of the study. On the other hand,
it is well known that motor disorders are the main
presentation of iNPH (Williams and Relkin, 2013).
In this study we administered an exhaustive neu-
ropsychological test battery in order to investigate
different cognitive domains; this is crucial for obtain-
ing a detailed cognitive profile (Devito et al., 2005;
Saito et al., 2011; Bugalho et al., 2014). In our opin-
ion, accurate cognitive characterization of patients
before shunt surgery is important from the perspec-
tive of outcome evaluation. Enrolling a homogeneous
population of iNPH patients may improve the predic-
tion of response to shunt surgery. Furthermore, as
previously underlined (Picascia et al., 2015), in this
setting there is a need for further studies with longer
follow-up periods and for closer interaction among
the different professionals involved).
146
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