Clinical Neurology and Neurosurgery 207 (2021) 106810

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Evaluation of the effect comorbid Parkinson syndrome on normal pressure

hydrocephalus assessment
Alexander Davis a, Seema Gulyani a, Lacie Manthripragada b, c, Mark Luciano c,
Abhay Moghekar a, Sevil Yasar a, d, *
a
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
b
Lacie Manthripragada, Advent Health Pediatric Neurosurgery, Orlando, FL, USA
c
Department of Neurosurgery, Johns Hopkins University Baltimore, MD, USA
d
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: The primary aim of the study was to assess the effect comorbid Parkinson syndromes have on results of
Normal pressure hydrocephalus CSF tap test (TT) and shunt outcomes for patients presenting with Normal Pressure Hydrocephalus (NPH). We
Lumbar puncture hypothesized that patients with possible NPH and comorbid Parkinson syndromes with Positive DaT scans will
Parkinsonism syndrome
not respond to CSF TT at the same rate as patients without comorbid Parkinson syndromes. Additionally, we
Gait
Cognition
followed a small number of patients with positive DaT scans who were shunted to assess long term outcome of
comorbid Parkinson syndromes.
Methods: Medical records and neurological exams of 251 patients were reviewed. In our analysis 101 patients
with no parkinsonian symptoms and no DaT scans were included as a control group, there were 52 patients with
DaT scans, 31 patients were positive (DaT-P). Gait measures were assessed before and after CSF TT using the
Wilcoxon matched-pairs signed-rank test or paired t-tests were used. To compare the effect of DaT-P and Control,
we used an ANCOVA controlling for age, sex, assistive device used, and past medical history effecting gait.
Results: There was not a significant difference in response between Control and DaT-P group. The Control group
improved on timed up and go (TUG) by 14.82%, DualTUG 16.35%, 10-meter Walk Test (10MWT) 18.13%,
MiniBEST 15.91%, and 6-minute Walk Test (6MWT) 13.96%, while the DaT-P group improved on TUG by
14.93%, DualTUG 17.24%, 10MWT 22.68%, MiniBEST 18.07%, and 6MWT 16.06%.
Conclusion: Our findings suggest that patients with possible NPH and suspected comorbid movement disorder,
showed similar improvement after diagnostic CSF TT compared to participants with no parkinsonian symptoms
present on exam.
Data availability statement: Data relevant to the study will be made available from the corresponding author upon
a reasonable request.

1. Introduction
Normal Pressure Hydrocephalus (NPH) is a neurological condition
caused by enlarged communicating ventricles. NPH is characterized by
the classical triad gait dysfunction, cognitive decline, and urinary in­
continence, with gait dysfunction being an essential symptom of the
triad [1–3]. NPH diagnosis is based on clinical presentation, neuro­
imaging, and response to cerebrospinal fluid (CSF) drainage (CSF tap
test [CSF TT]) and is often a diagnosis of exclusion [4]. NPH is treated
with a shunt that diverts CSF flow with clinical improvement in 24–80%
of cases immediately after shunt surgery and 50% after a 3-year
follow-up [5]. The wide range of effectiveness may be partially due to
the presence of comorbid neurodegenerative and/or cerebrovascular
diseases. The inadequate sensitivity and specificity for assessing
shunt-responsiveness in the presence of any of these comorbidities
complicate the interpretation of long-term clinical outcomes of shunt
placement [6].
One of the most common comorbidities for NPH is Parkinson syn­
dromes, with approximately 46.5–71% of patients with NPH also having
evidence to suggest comorbid Parkinson syndromes [7,8]. Even with
how common comorbid Parkinson syndromes are with NPH, evidence is
sparse regarding the effect Parkinson syndromes have on diagnostic CSF

* Correspondence to: Johns Hopkins University School of Medicine, Baltimore, MD, USA.

https://doi.org/10.1016/j.clineuro.2021.106810
Received 31 March 2021; Received in revised form 6 July 2021; Accepted 6 July 2021
Available online 10 July 2021
0303-8467/© 2021 Elsevier B.V. All rights reserved.
A. Davis et al.
TT [6].
New advances in imaging technology have helped clinicians in the
differential diagnosis of Parkinson’s syndromes. 123I-ioflupane single-
photon emission computed tomography (SPECT) uses SPECT of the
dopamine transporter (DaT). The diagnostic accuracy of DaT scans when
the reference standard is the final pathological diagnosis is very high,
with both sensitivity and specificity being in the high 90s for Parkinson
syndromes [9].
This preliminary study aims to assess the effect Parkinson syndromes
have on the diagnosis of patients with NPH. We hypothesized that pa­
tients with Parkinson syndromes, defined as parkinsonian symptoms
present on physical exam and abnormal DaT scan, will not respond to a
CSF TT at the same rate as patients without Parkinson syndromes. In this
study, we evaluated the CSF TT response in patients with parkinsonian
symptoms and abnormal DaT scans compared to patients without
parkinsonian symptoms. The response was assessed using pre- and post
CSF TT for the 10 Meter Walk Test [10], Timed Up & Go [11], Dual
Timed Up & Go [12], and 6-Minute Walk Test [13], and Mini-Balance
Evaluation Systems Test (MiniBEST) [14]. Additionally, we followed a
small number of patients with abnormal DaT scan who underwent shunt
placement.
2. Methods
2.1. Participants
A retrospective chart review of 251 patients who underwent a CSF TT
at the Johns Hopkins Center for CSF Disorders was completed. All pa­
tients included in the study were over the age of 60 and seen within the
departments of Neurosurgery and Neurology, between December 2015
and July 2019. Patients underwent a CSF TT if they had cerebral ven­
triculomegaly, the presence of gait, cognitive, and/or urinary dysfunc­
tion to evaluate presence of possible NPH.
Ventriculomegaly was defined as having EVAN’s index (EI) of >0.30,
which is the ratio of maximum width of the frontal horns of the lateral
ventricles and maximal internal diameter of skull [16] We used EI which
in a recent study by Ryska et al. [15] has been shown to reliable
discriminate between iNPH and healthy controls when it compared 15
proposed neuroimaging biomarkers of iNPH. However, this study also
found that caudocranial measures (callosal angle, supraventricular brain
tissue width, disproportionately enlarged subarachnoid space hydro­
cephalus, brain-to-ventricle ratio) were superior to EI [15].
The study was approved by the Johns Hopkins IRB: Cerebrospinal
Fluid Disorders Biorepository & Adult Hydrocephalus Clinical Research
Network. Being a retrospective study involving only data extraction and
Fig. 1. Flowchart.
2
Clinical Neurology and Neurosurgery 207 (2021) 106810
analysis, informed consent was waived by the IRB. Data once extracted
was anonymized for analysis.
Medical records, including neurological exams were reviewed
(Fig. 1). First, the 199 patients who did not undergo a DaT scan medical
records were reviewed to determine if parkinsonian symptoms were
present on exam as defined by the presence of: bradykinesia, tremor,
freezing gait, increased muscle tone, or cogwheeling. Shuffling gait and
postural instability were not included due to them also being symptoms
of NPH. Ninety-eight patients were excluded from our analysis due to
having at least one parkinsonian symptom and not having had a DaT
scan. Leaving 101 patients in the analysis who did not present with any
parkinsonian symptoms and did not undergo a DaT scan (Control).
52 patients had parkinsonian symptoms present on exam and also
underwent DaT scan. Of the 52 patients with a DaT scan, 31 patients had
an abnormal (positive; DaT-P) scan, read by radiologist as abnormal,
and were included in our analysis, while 21 patients had a normal
(negative) DaT scan, read by radiologist as normal, thus were not
included in our analysis. Due to the small number of participants with
negative DaT scan (n = 21) and large variability in the test results (TUG:
M = 36.6 + 41.9), we were unable to do a comparative analysis.
Of the 31 patients with positive DaT scans, 8 patients were treated
with carbidopa-levodopa at least 6 months before the CSF TT with no
significant improvement in gait following treatment initiation. 12 pa­
tients were started on carbidopa-levodopa after the TT and 11 patients
were never treated with carbidopa-levodopa or carried diagnosis of
movement disorder.
2.2. Outcome measures
All patients underwent a CSF TT via lumbar puncture (LP) in
outpatient clinic setting. LPs were done using a Quincke needle (22G) at
the L3-L4 or L4-L5 interspace as is standard of care, and 40 mL of CSF
was drained and was sent for routine laboratory studies.
Gait assessments were completed by physical therapists in hallways
with smooth floors. Assistive devices were used when required for safe
ambulation, patients used the same assistive device for all trials. Pre CSF
TT assessments were completed between 1 and 4 h before the beginning
of the drain. Post CSF TT assessments began when the patient was
medically cleared to walk after the LP, approximately 60 min after the
completion of the drain. Gait measures were divided into three domains
- velocity, balance, and endurance.
2.2.1. Gait velocity
For all gait velocity measures, patients were instructed to walk “As
quickly as you can, safely.” 10-Meter Walk Test (10MWT): patients
A. Davis et al. Clinical Neurology and Neurosurgery 207 (2021) 106810

started standing up, walked ten meters in a straight line, and stopped Table 1
[10]. Timed Up & Go (TUG): patients started seated in a chair with Demographics information of patients.
armrests; stood up, walked ten feet, turned 180 degrees; walked back, Total N = 251 Control DaT-P N = 31 p
and sat down in the chair [11]. DualTUG: identical to the TUG except (Mean/SD or N = 101 (Mean/SD or
while patients walked they performed a serial subtraction of three [12]. %) (Mean/SD or %)
%)
All gait velocity measures used the time required to complete measured
to hundredths of a second as the final score. Age (years) 73.83 (8.67) 72.61 (9.74) 74.33 (6.47) 0.344
Sex (male) 60.16% 54.46% 64.52% 0.323
BMI (kg/cm2) 27.61 (4.46) 28.09 (4.56) 27.04 (4.21) 0.279
2.2.2. Endurance Evans Index 0.370(0.044) 0.376(0.045) 0.354(0.04) 0.010
6-Minute Walk Test (6MWT): Patients walked as far as they were Race (Caucasian) 89.71 91.09 85.71 0.516
capable of in six minutes [13]. The final score for the 6MWT was total Education (years) 0.046
distance walked measured in feet. <16 32.22% 33.67% 18.52%
12–16 40.59% 44.9% 37.04%
>16 27.20% 21.43% 44.4%
2.2.3. Balance Assistive device 0.197
Mini-Balance Evaluation Systems Test (MiniBEST): is a dynamic None 44.62% 52.48% 41.94%
measure of balance consisting of fourteen items all scored from 0 to 2. Cane 28.69% 27.72% 22.58%
Patients attempted tasks such as rising from a chair with their arms Walker 26.69% 19.8% 35.48%
Past medical 54.18% 56.44% 48.39% 0.431
crossed, attempting to raise their heels off the ground while standing history effecting
upright, etc. The maximum score was 28 points with a higher total score gait
indicating better balance [14]. Baseline gait
testing 251 101 31 0.189
TUG 20.77(14.69) 16.8(10.03) 20.90(15.39) 0.234
2.3. Statistical analyses
DualTUG 28.16(19.87) 23.79(15.16) 29.12(23.01) 0.159
10MWT 14.77(10.32) 13.02(8.73) 15.39(11.73) 0.470
Before defining the data analysis plan, we knew that we had MiniBEST 15.19(5.14) 15.90(4.97) 15.16(5.0) 0.125
attempted temporary drains on patients with extreme levels of impair­ 6MWT 841.48 926.89 790.92
ment that go beyond what would be consistent with suspected NPH. To (453.91) (418.28) (455.78)

address this issue outliers any score that was greater than three standard DaT-P = patients with parkinsonian symptoms present and positive DaTscan.
deviations away from the mean was considered an outlier [17] and were Control = patients without parkinsonian symptoms and no DaTscan.
removed based on pre-drain scores. Past medical history possibly effecting gait: stroke, transient ischemic attack,
Baseline demographic characteristics between Control and DaT-P peripheral neuropathy, osteoarthritis, degenerative joint disease, and spinal
were compared using unpaired t-tests and Pearson’s chi-squares. To disorders.
Timed Up & Go (TUG), seconds.
assess the normality of the measures the Shapiro-Wilk test was used. The
Dual Timed Up & Go (DualTUG), seconds.
TUG, DualTUG, and 10MWT were not normally distributed, the Min­
10 Meter Walk test (10MWT), seconds.
iBEST and 6MWT were normally distributed. For the TUG, DualTUG, Mini-Balance Evaluation Systems test (MiniBEST), points.
and 10MWT, the Wilcoxon rank-sum test was used to assess if there was 6-Minute Walk test (6MWT), feet.
a difference at pre-drain or post-drain between Dat-P and Control.
To assess if there was a significant change in score following the CSF
DaT-P patients having smaller EI and higher education level than the
TT for the TUG, DualTUG, and 10MWT, pre and post CSF TT means were
Control patients (Table 1), and Control group having more osteoarthritis
compared using the Wilcoxon matched-pairs signed-rank test. For the
and degenerative joint disease and/or other spinal disorders (data not
MiniBEST and 6MWT, unpaired t-tests were used to assess if there was a
shown).
difference at pre or post CSF TT between DaT-P and Control. To assess if
there was a significant change in score following the CSF TT for the
3.2. Outcome measures
MiniBEST and 6MWT, pre and post CSF TT means were compared using
paired t-tests.
Table 2 shows test results after the CSF TT for the outcome measures.
As a secondary analysis, to compare the effect of DaT-P and Control,
Both Control and DaT-P groups improved significantly in all measures;
we used an ANCOVA controlling for age, sex, assistive device used, and
TUG by 2.49 s and 3.12 s, respectively; DualTUG by 3.89 s and 3.12 s,
past medical history affecting gait (stroke, transient ischemic attack,
10MWT by 2.36 s and 3.49 s, MiniBEST by 2.53 points and 2.74 points,
peripheral neuropathy, osteoarthritis, degenerative joint disease, and
and 6MWT by 129.4 feet and 127 feet.
spinal disorders). The significance level for all tests was set to p < 0.05.
Table 3 shows percent change in test results the CSF TT in all indi­
vidual measures between Control and DaT-P group. There was not a
3. Results
significant difference in response between Control and DaT-P group. The
control group improved on TUG by 14.82%, on DualTUG by 16.35%, on
3.1. Participants
10MWT 18.13%, on MiniBEST by 15.91% and on 6MWT by 13.96%,
while the DaT-P group improved on TUG by 14.93%, on DualTUG by
Table 1 shows baseline demographics. Patients were 73.04 years old,
17.24%, on 10MWT 22.68%, on MiniBEST by 18.07% and on 6MWT by
were mostly Caucasian (89.92%) and highly educated with 69.60%
16.06%.
having higher then high school education, 50% using an assistive device
In our sub-analysis, we compared DaT-P participants reporting use of
and 54.55% reporting past medical history which could also affect gait.
carbidopa-levodopa, either before or after CSF TT, to control group,
In terms of specific comorbidities, of the 251 participants 18 (7%) had
using ANCOVA and it did not change our findings (data not shown).
history of stroke and/or transient ischemic attack, 11 (4%) had pe­
Additionally, when excluding from our analysis patients treated with
ripheral neuropathy, 80 (32%) had osteoarthritis, 58 (23%) had
carbidopa-levodopa before CSF TT, patients with a positive DaT scan
degenerative joint disease and/or other spinal disorders, 9 (3%) had
still improved (data not shown).
movement disorder and 8 (3%) had Alzheimer’s disease (AD) and/or
other dementia when they came for NPH work-up. For baseline char­
acteristics, there was only a significant difference found between DaT-P
and Control patients for the Evans Index (EI) and education level, with

3
A. Davis et al. Clinical Neurology and Neurosurgery 207 (2021) 106810

Table 2
Change in test results after CSF TT.
Total N = 251 Control N = 101 DaT-P N = 31

Pre CSF TT Post CSF TT Pre vs Post CSF Pre CSF TT Post CSF TT Pre vs Post CSF Pre CSF TT Post CSF TT Pre vs Post CSF
TT TT TT

TUG 20.77(14.69) 17.16(11.31) <0.001 16.8(10.03) 14.31(7.7) <0.001 20.90(15.39) 17.78(13.92) <0.001
DualTUG 28.16(19.87) 22.98(14.90) <0.001 23.79(15.16) 19.90(10.95) <0.001 29.12(23.02) 24.10(21.11) <0.001
10MWT 14.77(10.32) 11.74(6.76) <0.001 13.02(8.73) 10.66(6.06) <0.001 15.39(11.73) 11.90(6.74) <0.001
MiniBEST 15.19(5.14) 17.89(4.87) <0.001 15.90(4.97) 18.43(4.74) <0.001 15.16(5.00) 17.90(4.60) <0.001
6MWT 841.48 974.11 <0.001 926.89 1056.29 <0.001 790.92 917.92 <0.001
(453.91) (485.31) (418.28) (450.05) (455.78) (502.16)

DaT-P = patients with parkinsonian symptoms present and positive DaTscan.

Control = patients without parkinsonian symptoms and no DaTscan.
Timed Up & Go (TUG), seconds.
Dual Timed Up & Go (DualTUG), seconds.
10 Meter Walk test (10MWT), seconds.
Mini-Balance Evaluation Systems test (MiniBEST), points.
6-Minute Walk test (6MWT), feet.

an undiagnosed comorbid Parkinson syndrome could undergo a CSF-TT.

Table 3
Percentage change after CSF-TT in all test results between groups.
Control % change after CSF DaT-P % change after CSF
TT (mean differenc) TT (mean difference)
TUG 14.82% (2.49) 14.93% (3.12)
DualTUG 16.35% (3.89) 17.24% (5.02)
10MWT 18.13% (2.36) 22.68% (3.49)
MiniBEST 15.91% (2.53) 18.07% (2.74)
6MWT 13.96% (129.4) 16.06% (127)
All analyses were adjusted for: age, sex, assistive device used, and past medical
history effecting gait (stroke, transient ischemic attack, peripheral neuropathy,
osteoarthritis, degenerative joint disease, and spinal disorders).
Significance level was set to p < 0.05.
Timed Up & Go (TUG). seconds.
Dual Timed Up & Go (DualTUG), seconds.
10 Meter Walk test (10MWT), seconds.
Mini-Balance Evaluation Systems test (MiniBEST), points.
6-Minute Walk test (6MWT), feet.
4. Discussion
Our study compared the CSF TT response of patients presenting with
suspected NPH, parkinsonian symptoms, and a positive DaT scan (DaT-
P) to patients presenting without parkinsonian symptoms (Control). We
hypothesized that patients with a positive DaT scan would not improve
following a CSF TT. Contrary to our hypothesis, we found that patients
with a positive DaT scan will improve on a CSF TT. Additionally, we
found that there was not a significant difference in CSF-TT response
between patients with a positive DaTscan and control patients. Simi­
larly, we found that at baseline, patients with a positive DaTscan were
not more impaired than the patients in the control group.
There is both physiological and experimental evidence to support
that dopamine deficiency is common in patients with NPH. Alterations
in post synaptic dopamine 2 (D2) receptors have been shown to be
altered in NPH patients [18]. There is evidence for metabolic distur­
bance in NPH such as reduced global and regional cerebral blood flow
(CBF), particularly in periventricular areas resulting in reduced
oxygenation in basal ganglia which could contribute to motor distur­
bances [19]. Few studies have seen success treating shunted patients for
potential comorbid parkinsonian symptoms with dopamine oral therapy
[8]. However, the effect comorbid Parkinson syndromes have on CSF-TT
is unknown.
The objective of this study was to assess the effect that potential
comorbid Parkinson syndromes have on a CSF-TT. In a clinical appli­
cation, NPH and Parkinson syndromes have overlapping symptoms that
can make differencing the two conditions difficult. This difficulty in
differentiating the two conditions makes it plausible that a patient with
We expected to find that patients with suspicion of a movement disorder
and a positive DaT scan would not improve at the same rates as patients
p- without suspicion of Parkinson syndrome following a CSF-TT. However,
value
we found that patients in the DaT-P group were not more impaired at
0.994 baseline and improved at the same rate following a CSF-TT. Patients
0.542 with a potential movement disorder not presenting with significantly
0.677
0.431
more impairment than their control counterparts improving on a CSF TT
0.466 could lead to patients being shunted who have an undiagnosed comor­
bid movement disorder [7,8]. This could partially explain the wide
range in shunt long term shunt outcome. Our study was not able to
answer the question of how comorbid Parkinson syndromes may effect
shunt outcome since our study only had eight patients with a positive
DaT scan that were shunted. Of these only five patients had a post-shunt
evaluation available, with a mean follow-up of 1.3 years, and the mean
percent change between pre shunt and post-shunt scores being 16%
improvement in the TUG and 31% improvement in the 10MWT. Due to
the small numbers of shunted participants in the DaT-P group, we
cannot make conclusions based on our data. Thus, we do not know if the
CSF-TT results will predict shunt outcome in these patients.
Due to the results of the study being contrary to the hypothesis, a
larger follow up study is needed to address limitations of this study
design. First, the study was small thus lacked power to detect difference
between DaT-P and control group. Second, while DaT scans have been
shown to be sensitive diagnostic tests with high sensitivity [9], we
cannot conclude that a patient has Parkinson syndrome without being
examined by a specialist. Third, DaT scans were only administered on
patients with suspicion of a movement disorder thus we may have
missed patients. While all patients underwent a neurological exam, we
do not know if patients in the control group who did not have suspicion
of a movement disorder have a positive DaT scan. Additionally, DaT
scans can be negative in some movement disorders such as vascular
Parkinsonism [20]. This may have resulted in and misclassification bias.
As well, the control group could have AD [21,22] or vascular brain
disease [22] which are common comorbidities in NPH and therefore
differed from the experimental group in a way that was unmeasured.
The strengths of our study include a large number of participants with
detailed and well-established quantitative measures of several gait,
balance, and endurance domains. The dataset we have is presently the
only published dataset with detailed gait testing and DaT scans for pa­
tients undergoing a CSF-TT.
In summary, contrary to our hypothesis, our findings suggest that
patients with possible NPH, parkinsonian symptoms and a positive DaT
scan, showed similar improvement after diagnostic CSF-TT when
compared to participants with no suspicion of a movement disorder. Our
study shows the first preliminary evidence that patients with suspected
NPH and potentially undiagnosed Parkinson syndrome can improve on

4
A. Davis et al.
CSF-TT at the same rate as patients without suspicion of a movement
disorder. This is important information; however, it is critical to follow
these patients to collect information on long-term shut outcome in these
patients with comorbid Parkinson syndromes to help to make informed
decisions. Additionally, our study needs to be replicated to address
limitations.
CRediT authorship contribution statement
Alexander Davis: Conceptualization, Methodology, Software, Sta­
tistical Analysis, Writing – original draft. Seema Gulyani: Conceptual­
ization, Writing – review & editing. Lacie Manthripragada, Mark
Luciano : Conceptualization, Writing – review & editing. Abhay Mog­
hekar: Conceptualization, Writing – review & editing. Sevil Yasar:
Conceptualization, Methodology, Statistical Analysis, Writing – original
draft and editing, Supervision.
Financial disclosures
Alexander Davis - Reports no disclosures; Seema Gulyani - Reports no
disclosures; Lacie Manthripragada - Reports no disclosures; Mark
Luciano – Reports no disclosures; Abhay Moghekar - Reports no dis­
closures; Sevil Yasar - Reports no disclosures.
Study Funded
Not applicable.
Conflict of interest
None.
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