Journal of Clinical Neuroscience xxx (2014) xxx–xxx

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Clinical Study

Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test Kyunghun Kang a, Pan-Woo Ko a, Myungwon Jin b,c, Kyoungho Suk b,c,1, Ho-Won Lee a,c,⇑,1 a

Department of Neurology, Kyungpook National University School of Medicine, 50 Samdeok-dong 2-ga, Jung-gu, Daegu 700-721, South Korea Department of Pharmacology, Kyungpook National University School of Medicine, Daegu, South Korea c Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu, South Korea b

a r t i c l e

i n f o

Article history: Received 19 August 2013 Accepted 13 November 2013 Available online xxxx Keywords: b amyloid Biomarker Cerebrospinal fluid Normal pressure hydrocephalus Phosphorylated-tau Predictive value of tests

a b s t r a c t Cerebrospinal fluid (CSF) biomarkers, including soluble amyloid b-42 (Ab-42) and phosphorylated-tau (P-tau), reflect core pathophysiological features of Alzheimer’s disease (AD). AD is frequently a concomitant pathology in older patients with idiopathic normal-pressure hydrocephalus (iNPH), and somewhat similar altered CSF dynamics exist in both AD and iNPH. We therefore investigated relationships between lumbar CSF biomarkers Ab-42 and P-tau and clinical parameters in iNPH patients, along with differences in these biomarkers between CSF tap test (CSFTT) responders and non-responders. Thirty-one iNPH patients (14 CSFTT responders and 17 CSFTT non-responders) were included in the final analysis. We found lower CSF Ab-42 correlated with poor cognitive performance (r = 0.687, p < 0.001 for Korean Mini Mental State Examination; r = 0.568, p = 0.001 for Frontal Assessment Battery; r = 0.439, p = 0.014 for iNPH grading scale [iNPHGS] cognitive score; r = 0.588, p = 0.001 for Clinical Dementia Rating Scale), and lower CSF P-tau correlated with gait dysfunction (r = 0.624, p < 0.001 for Timed Up and Go Test; r = 0.652, p < 0.001 for 10 meter walking test; r = 0.578, p = 0.001 for Gait Status Scale; r = 0.543, p = 0.002 for iNPHGS gait score). In subgroup analysis, CSF P-tau/Ab-42 ratios were significantly higher in CSFTT non-responders compared to responders (p = 0.027). Two conjectures are suggested. One, CSF biomarkers may play different and characteristic roles in relation to different iNPH symptoms such as cognition and gait. Two, comorbid AD pathology in iNPH patients may affect the response to the CSFTT. Larger studies using combinations of other biomarkers associated with AD would be necessary to evaluate these hypotheses. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Idiopathic normal-pressure hydrocephalus (iNPH) is regarded as a potentially treatable dementia. It is an adult-onset syndrome of uncertain origin, with symptoms of gait disturbance, cognitive deterioration and urinary incontinence, and involves non-obstructive enlargement of the cerebral ventricles along with normal cerebrospinal fluid (CSF) pressure [1]. Alzheimer’s disease (AD) is frequently concomitant with iNPH, with one study finding that 89% of iNPH patients exhibited AD pathology [2]. Moreover, both AD and iNPH are reported to exhibit somewhat similar altered CSF dynamics, and some reports suggest there may be an overlapping pathology [3]. And although the role of AD in patients with iNPH is debated, one study suggested AD ⇑ Corresponding author. Tel.: +82 53 200 3271; fax: +82 53 200 3299. 1

E-mail address: [email protected] (H.-W. Lee). These authors have contributed equally to the manuscript.

pathology contributed to the symptomatology of iNPH and had an adverse effect on shunt surgery outcomes [4]. CSF biomarkers measured with enzyme-linked immunosorbent assay (ELISA), including soluble amyloid b-42 (Ab-42) and phosphorylated-tau (P-tau), have been well-established and internationally validated in diagnosing AD [5], and the specific combination of low CSF Ab-42 and elevated CSF P-tau is regarded as a biomarker signature of AD [6]. Ab-42 and P-tau are believed to reflect core pathophysiological features of the disease [7], and this view has been validated in post mortem studies [8,9]. Similarly, CSF biomarker studies on iNPH patients have been carried out in several laboratories, but with only moderate agreement in the results. Most studies on iNPH patients report decreased CSF Ab-42 levels [10–14], although one reported no change [15]. Studies on iNPH patients have tended to report decreased CSF P-tau levels [10,11,15], although one reported increased levels [13], and one reported no change [14].

http://dx.doi.org/10.1016/j.jocn.2013.11.039 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kang K et al. Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.11.039

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K. Kang et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx

There has been little investigation into specific relationships in iNPH patients between CSF biomarkers and clinical characteristics. One study investigated the relationship between cognitive deficits and CSF Ab-42 and total tau levels in iNPH patients [12]. Another study analyzed the correlation of P-tau with Mini Mental State Examination score [13]. In both studies, no statistically significant relationships were found, and there have been no iNPH studies correlating CSF biomarkers and gait to our knowledge. Finally, the CSF tap test (CSFTT) response is regarded as an important marker for the prediction of shunt effectiveness in patients with iNPH and a valuable characteristic for understanding iNPH patients [16]. There may be unknown relevant relationships between CSF biomarkers and CSFTT response. One hypothesis is that AD pathology may affect CSFTT response. Analyzing the Ab42/P-tau ratio between CSFTT responders and non-responders might shed light on this issue. We investigated relationships between CSF biomarkers, including Ab-42 and P-tau, and clinical parameters in iNPH patients. We also evaluated differences in these CSF biomarkers in iNPH patients relative to the outcome of their CSFTT. We hypothesized that there may be specific relationships between CSF biomarkers and clinical characteristics, and that the biomarker signature of AD, the Ab-42/ P-tau ratio, may be different according to CSFTT response. 2. Methods 2.1. Participants Participants were recruited from patients who visited the Center for Neurodegenerative Diseases of Kyungpook National University Hospital, South Korea from July 2011 to February 2013. Informed consent was obtained from all participants or their caregivers prior to study participation. This study was approved by the Institutional Review Board at our institution. From the individuals classified as iNPH according to the criteria proposed by Relkin et al. [17], 35 patients agreed to enroll in this study. Patients had to be older than 40 years of age with an insidious progression of symptoms (gait disturbance, plus at least one other area of impairment in either cognition or urinary symptoms, or both) for at least 6 months and have normal CSF opening pressure. Brain MRI of all iNPH patients showed widening of the ventricles (Evan’s ratio >0.3) and no obstruction of CSF flow. Patients with stroke, neurological, metabolic, or neoplastic disorders that might produce dementia symptoms or parkinsonism, a recent history of heavy alcohol use, or a history of hospitalization for a major psychiatric disorder, were excluded. No participant had a related antecedent event, such as head trauma, intracerebral hemorrhage, meningitis, or any other known cause of secondary hydrocephalus. 2.2. Assessing illness severity The patients’ general cognitive state and severity of dementia were evaluated by means of the Korean Mini Mental State Examination (K-MMSE) and Clinical Dementia Rating Scale (CDR) [18,19]. The Frontal Assessment Battery (FAB), a simple tool designed for assessing frontal lobe symptoms, was used [20]. The length of time taken to complete the Trail Making Test Part A (TMT-A), a common neuropsychological test to evaluate psychomotor speed, often used for patients with iNPH, was recorded [21]. We also utilized the iNPH grading scale (iNPHGS), a clinicianrated scale used to assess the severity of each fundamental symptom of iNPH (cognitive impairment, gait disturbance and urinary disturbance) after an unstructured interview with patients and caregivers [21].

Gait assessment included measurements on the Timed Up and Go test (TUG) and the 10 meter walking test [21,22]. They were performed four times consecutively and the mean score was used. The features of gait disturbance related to iNPH were also estimated using the Gait Status Scale (GSS) [21]. 2.3. CSFTT A lumbar tap removing 30–50 ml of CSF was performed in all iNPH patients. CSF pressure was measured at the site of puncture. After the tap, all patients were re-evaluated using the iNPHGS, K-MMSE and TUG test. Changes in gait were repeatedly evaluated over 7 days after the tap, while changes in cognition and urination were evaluated at 1 week [23]. Response to the CSFTT was defined using the iNPHGS, TUG and K-MMSE. Responders were defined as showing improvement of one point or more on the iNPHGS, more than 10% improvement in time on the TUG test, or more than three points improvement on the K-MMSE [16]. 2.4. Laboratory CSF analysis CSF samples were collected in the morning through a lumbar puncture with the patient in a recumbent position. Bloody or cloudy samples were rejected. All CSF samples were collected in polypropylene tubes, centrifuged, aliquoted, and frozen at 80 °C until analyzed. The levels of Ab-42 and P-tau in the CSF were measured by commercially available single-parameter ELISA kits (Innotest b-Amyloid(1–42), Innotest Phosphotau(181P); Innogenetics, Ghent, Belgium). In each assay, CSF samples and the appropriate controls were tested following the instructions provided by the manufacturer. All measurements were gathered from duplicated assays. The reference concentration ranges of the test kits were Ab-42 = 125–2000 pg/ml, and P-tau = 15.6–500 pg/ml. 2.5. Statistical analyses The Statistical Package for the Social Sciences version 21.0.0 (SPSS, Chicago, IL, USA) was used for analysis of data. Spearman’s correlations were employed to investigate the relationship between CSF biomarkers, clinical measures, and MRI features in iNPH. The demographic data, clinical characteristics, CSF drainage volume and CSF opening pressure during the tap test and MRI features were compared in iNPH patients between CSFTT responders and non-responders. Fisher’s exact and chi-squared tests were used to compare categorical variables, while the Mann–Whitney U test was used to compare continuous variables. We also compared CSF biomarkers, including Ab-42, P-tau, and P-tau/Ab-42 ratios, between CSFTT responders and non-responders using Student’s t-test. The statistical significance level was set at p < 0.05. Data are presented as mean ± standard deviation. 3. Results 3.1. Baseline clinical characteristics, neuropsychological testing, and CSF biochemical profile Four participants who completed the CSFTT were excluded due to bloody or cloudy CSF samples. The remaining 31 iNPH patients constituted the final sample for analysis. The study participants included 18 men and 13 women; the mean age was 73.5 ± 5.2 years. In 26 (83.9%) patients, gait disturbance was the initial presenting symptom. All 31 patients had gait disturbance, 30 (96.8%) had cognitive disturbance, and 16 (51.6%) had urinary

Please cite this article in press as: Kang K et al. Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.11.039

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incontinence at the time of assessment. The mean duration of symptoms was 2.1 ± 1.1 years. At baseline, the mean K-MMSE score was 17.1 ± 6.6. The mean subscale scores of iNPHGS were as follows: gait disturbance = 1.7 ± 0.9, cognitive impairment = 2.8 ± 0.6, and urinary disturbance = 1.1 ± 1.2. Of the 31 patients tested at baseline, 14 (45.2%) presented with the full triad of symptoms. The mean value of CSF Ab-42 was 480.63 pg/ml (median: 405.00 pg/ml), which is lower than the control reference value given by the manufacturers (median: 675 pg/ml) [24]. The P-tau levels in CSF had a mean of 34.49 pg/ml (median: 26.52 pg/ml), which was lower than the median value for P-tau in the control reference (median: 51 pg/ml) provided by the manufacturer [24]. 3.2. Correlations of CSF biomarkers, clinical measures and MRI features in iNPH In the whole sample, lower CSF Ab-42 levels correlated significantly with a lower K-MMSE score (r = 0.687, p < 0.001) and FAB score (r = 0.568, p = 0.001), as well as a higher iNPHGS cognitive score (r = 0.439, p = 0.014) and CDR score (r = 0.588, p = 0.001), whereas CSF P-tau levels did not correlate with these scores. Higher CSF P-tau/Ab-42 ratios were associated with a lower K-MMSE score (r = 0.461, p = 0.009) and higher CDR score (r = 0.407, p = 0.023). Lower levels of CSF P-tau correlated with a higher TUG score (r = 0.624, p < 0.001), 10 meter walking test score (r = 0.652, p < 0.001), GSS score (r = 0.578, p = 0.001), and iNPHGS gait score (r = 0.543, p = 0.002). No significant correlations were seen between CSF Ab-42 concentrations and gait tests (Table 1). 3.3. CSFTT responders versus non-responders in iNPH patients The demographic data, clinical characteristics, CSF drainage volume and CSF opening pressure during the tap test for the CSFTT responders and non-responders are presented in Table 2. Among the 14 CSFTT responders, 12 patients showed an improvement in the TUG (85.7%), five patients showed an improvement in the K-MMSE (35.7%), and eight patients showed an improvement in the iNPHGS (57.1%). We did not find any significant differences for the iNPHGS, TUG, 10 meter walking test, GSS, or TMT-A. MRI Table 1 Correlations between clinical measures, MRI features and cerebrospinal fluid biomarkers in idiopathic normal-pressure hydrocephalus patients Tests

Correlation coefficients Ab-42

P-tau

P-tau/Ab-42 ratio

K-MMSE FAB TMT-A CDR

0.687b 0.568b 0.225 0.588b

0.104 0.113 0.177 0.043

0.461b 0.312 0.014 0.407a

iNPHGS Gait disturbance Cognition impairment Urinary incontinence

0.017 0.439a 0.208

0.543b 0.047 0.059

0.337 0.317 0.090

TUG 10 meter walking test GSS

0.246 0.324 0.109

0.624b 0.652b 0.578b

0.232 0.156 0.282

Evan’s ratio

0.138

0.163

0.195

Significant results are displayed in bold. Ab-42 = amyloid b-42, CDR = Clinical Dementia Rating Scale, FAB = Frontal Assessment Battery, GSS = Gait Status Scale, K-MMSE = Korean version of Mini Mental State Examination, iNPHGS = idiopathic Normal-Pressure Hydrocephalus Grading Scale, P-tau = phosphorylated-tau, TMT-A = Trail Making Test Part A, TUG = Timed Up and Go test. a p < 0.05, Spearman’s correlation. b p < 0.01, Spearman’s correlation.

Table 2 Demographic data, clinical data, and MRI features for cerebrospinal fluid tap test responder and non-responder idiopathic normal-pressure hydrocephalus patients Characteristics

Tap test responder (n = 14)

Tap test nonresponder (n = 17)

Male sex Age, years Duration of symptoms, years Education, years History of hypertension History of diabetes History of lipid disorder

9 (64.3) 72.7 ± 4.8 2.1 ± 1.0 8.6 ± 4.7 5 (50.0) 7 (50.0) 2 (14.3)

9 (52.9) 74.2 ± 5.5 2.2 ± 1.3 6.4 ± 6.2 8 (47.1) 4 (23.5) 5 (29.4)

Initial symptoms Gait disturbance Cognitive impairment

13 (92.9) 1 (7.1)

13 (76.5) 4 (23.5)

Full-blown symptoms Gait disturbance Cognitive impairment Urinary incontinence

14 (100) 13 (92.9) 8 (57.1)

17(100) 17 (100) 8 (47.1)

Clinical triad present Drainage volume of CSF CSF opening pressure, cm H2O ApoE e4+/e4

7 (50.0) 39.3 ± 4.3 9.6 ± 11.2 3/9

7 (41.2) 37.8 ± 5.5 11.2 ± 2.9 5/10

iNPHGS Gait disturbance Cognition impairment Urinary incontinence TUG 10 meter walking test GSS K-MMSE CDR FAB TMT-A

1.9 ± 0.9 2.7 ± 0.5 1.1 ± 1.0 17.6 ± 12.3 23.9 ± 44.7 6.4 ± 3.1 20.0 ± 5.6 0.9 ± 0.4 8.9 ± 5.6 232.7 ± 127.2

1.5 ± 0.9 2.8 ± 0.6 1.1 ± 1.4 27.4 ± 35.1 32.3 ± 53.7 5.4 ± 4.2 14.6 ± 6.6a 1.5 ± 0.7a 5.6 ± 3.5b 260.5 ± 172.7

0.37 ± 0.04 9 (64.3)

0.34 ± 0.03a 10 (58.8)

Evan’s ratio Narrowing of the CSF space at high convexity

Data are presented as number (%) or mean ± standard deviation. Significant effects are displayed in bold. ApoE = apolipoprotein E, CDR = Clinical Dementia Rating Scale, CSF = cerebrospinal fluid, FAB = Frontal Assessment Battery, GSS = Gait Status Scale, iNPHGS = idiopathic Normal-Pressure Hydrocephalus Grading Scale, K-MMSE = Korean version of Mini Mental State Examination, TMT-A = Trail Making Test Part A, TUG = Timed Up and Go test. a p < 0.05, Fisher’s exact and chi-squared tests or Mann-Whitney U test. b p < 0.01, Fisher’s exact and chi-squared tests or Mann-Whitney U test.

findings, including narrowing of the CSF spaces at the high convexity, did not differ between responders and non-responders. However, CSFTT non-responders had poorer cognitive performance measured with the K-MMSE, CDR, and FAB and a smaller Evan’s ratio compared to the responders. Furthermore, the CSFTT non-responders, when compared to responders, tended to show lower Ab-42 and higher P-tau levels in CSF (Table 3, Fig. 1A, B). Relative to the CSFTT responders, non-responders had a significantly higher CSF P-tau/Ab-42 ratio (Table 3, Fig. 1C).

4. Discussion The three important findings of this iNPH study were (1) lower CSF Ab-42 levels significantly correlated with poor cognitive performance, measured by the K-MMSE, FAB, iNPHGS cognitive score, and CDR; (2) lower CSF P-tau levels significantly correlated with gait dysfunction, as measured by the TUG, 10 meter walking test, GSS, and iNPHGS gait score; and (3) CSF P-tau/Ab-42 ratios were significantly higher in CSFTT non-responders compared to responders. Ab is a well-known major component of neuritic plaques in AD [25], but its relationship to iNPH is less certain. Deterioration in

Please cite this article in press as: Kang K et al. Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.11.039

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Table 3 Cerebrospinal fluid levels of amyloid b-42 and phosphorylated-tau for cerebrospinal fluid tap test responder and non-responder idiopathic normal-pressure hydrocephalus patients Tap test responder (n = 14)

Tap test non-responder (n = 17)

p value

Ab-42 (pg/ml) Mean ± SD Median

539.65 ± 271.32 496.98

432.02 ± 259.61 380.64

0.270

P-tau (pg/ml) Mean ± SD Median

30.09 ± 19.50 24.10

38.12 ± 24.10 35.97

0.323

P-tau/Ab-42 ratio Mean ± SD Median

0.07 ± 0.04 0.05

0.10 ± 0.04 0.10

0.027

CSF markers

Significant effects using Student’s t-test are displayed in bold. Ab-42 = amyloid b-42, CSF = cerebrospinal fluid, P-tau = phosphorylated-tau, SD = standard deviation.

CSF dynamics can cause Ab deposition [3,26], and Ab deposition and subsequent neurodegeneration are likely to occur in the iNPH brain [13]. Like AD patients, many studies on iNPH patients report decreased CSF Ab-42 levels compared to controls [11,14]. In our study lower CSF Ab-42 levels were significantly associated with cognitive impairment in iNPH patients. Previous iNPH studies found no correlations between cognitive deficits and CSF Ab-42

levels, however there are a few differences between the studies [12]. Our study had more participants, which may allow for more reliable statistical analysis. Our participants also had a shorter disease duration, which might signify earlier stages of the disease. It was reported that an increased amyloid burden is associated with decreased cognitive performance in cognitively normal individuals and early stages of AD, and this bears some connection with our result [27,28]. Some previous iNPH studies report lower than normal total tau or P-tau concentrations [10–12] and negative correlations of total tau levels with symptom duration [12]. These findings might be explained by low tau levels representing a state of irreversible and advanced degeneration in iNPH patients [12]. CSF total tau and P-tau levels did not correlate with cognitive deficits in previous studies [12,13], and our results are the same. However, to the authors’ knowledge, there has been no study on the relationship between CSF P-tau and gait in iNPH patients. Our result was that lower levels of CSF P-tau significantly correlated with gait dysfunction in iNPH patients. This may suggest a different and more complicated metabolism for tau protein in the iNPH brain compared with AD. Further studies on iNPH patients with larger study populations would be needed to establish this hypothesis. Our third main result was that among iNPH patients in our study CSF P-tau/Ab-42 ratios were greater in CSFTT non-responders compared to responders (p = 0.027). It is well-known that a high CSF P-tau/Ab-42 ratio is closely related to the underlying pathological mechanisms of AD [6]. It is therefore possible that

Fig. 1. Box and whisker plots comparing the cerebrospinal fluid (CSF) levels of biomarkers (A) amyloid b-42, (B) phosphorylated-tau and (C) amyloid b-42/phosphorylatedtau ratio in CSF tap test responder and non-responder idiopathic normal pressure hydrocephalus patients. For each plot, the horizontal line within each box shows the median value. Regions above and below the black line show the upper and lower quartiles, respectively. The vertical lines extend to the minimum and maximum values with outliers shown as open circles.

Please cite this article in press as: Kang K et al. Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.11.039

K. Kang et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx

the degree of coexistent AD pathology may influence responses to the CSFTT; however, to our knowledge this is the first study to investigate this link and significant further research would be needed to validate this hypothesis. Somewhat surprisingly, there were no statistically significant differences between responders and non-responders with regard to demographic data, most of the clinical characteristics, CSF drainage volume, and CSF opening pressure during the test. Additionally, our measurements of the narrowing of the CSF spaces at the high convexity, as shown on MRI, did not reveal statistically significant differences between CSFTT responders and non-responders. Our supplemental results were that CSFTT non-responders had poorer cognitive performance and a smaller Evan’s ratio compared to responders, but that CSFTT responders and non-responders had similar gait performance. This suggests the further hypothesis that cognitive symptoms may be predominate in the overall clinical picture of patients who are affected by comorbid AD and iNPH [29]. We tried to reduce the potential bias from clinical evaluation before and after the CSFTT by using various objective grading scales, instead of subjective reports by patients or caregivers, and repeatedly evaluating changes in gait over 7 days. The Japanese standards are generally considered to be popular and reasonable criteria in Asia for evaluating response to the CSFTT, and these criteria were used to identify responders in our study [16,23]. Our study is different from most previous studies on CSF biomarkers for iNPH with respect to the analysis of correlations between CSF markers, clinical characteristics, and neuropsychological profiles. To our knowledge, there have been only two studies investigating the correlation between CSF biomarkers and neuropsychological profiles in iNPH patients, but these previous studies included only 10 or 23 iNPH participants and did not perform responder/nonresponder subgroup analysis [12,13]. One limitation of our study is that, for ethical reasons, we did not have a normal control group, so we could not compare the CSF biomarkers of iNPH patients against controls, and only iNPH responder/non-responder analysis was possible. A second limitation was that we did not measure other AD biomarkers in our iNPH patients. As a result, we could only speculate about the possibility of greater comorbidity of AD amongst non-responders as opposed to responders. A third limitation is that this study included a small number of participants. Additional studies with larger study populations, including normal control subjects, are needed.

5. Conclusion Our study showed that lower CSF Ab-42 correlated significantly with poor cognitive performance, whereas lower levels of CSF Ptau correlated with gait dysfunction in iNPH patients. Each of these CSF biomarkers may play a different and characteristic role for different categories of symptoms such as cognition and gait, respectively. iNPH patients in our study showed statistically significant differences in CSF P-tau/Ab-42 ratios depending on their response to the CSFTT. Comorbid AD pathology may adversely influence the response to the CSFTT in iNPH patients. Larger studies using combinations of other biomarkers associated with AD would be necessary to evaluate these hypotheses. Analysis of the biochemical and clinical profiles of iNPH patients may help us understand their associations and potentially any underlying pathophysiological interrelationships.

Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

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Acknowledgements We thank Wade Martin of Medical Research International for the editorial revision of this manuscript. This research was supported by Samil Pharmaceuticals, the Converging Research Center Program through the Ministry of Science, ICT and Future Planning, Korea (2013K000364), and the Bio & Medical Technology Development Program and Basic Science Research Program of the National Research Foundation (NRF) funded by the Korean government (MEST) (No. 2012M3A9B6055414, 2012-0009328).

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Please cite this article in press as: Kang K et al. Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.11.039

Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test.

Cerebrospinal fluid (CSF) biomarkers, including soluble amyloid β-42 (Aβ-42) and phosphorylated-tau (P-tau), reflect core pathophysiological features ...
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