The CERAD Neuropsychological Battery in Patients with Idiopathic Normal Pressure Hydrocephalus Compared with Normal Population and Patients with Mild Alzheimer’s Disease

Abstract

Background:

The usefulness of CERAD Neuropsychological Battery for describing the cognitive impairment in idiopathic normal pressure hydrocephalus (iNPH) is unknown.

Objective:

To compare the cognitive profile of patients with iNPH to patients with mild Alzheimer’s disease (AD) and age-matched cognitively healthy individuals by using the CERAD-NB.

Methods:

We studied CERAD-NB subtest results, including the Mini-Mental State Examination (MMSE), between 199 patients with probable iNPH, 236 patients with mild AD, and 309 people with normal cognition, using age, education, and gender adjusted multivariate linear regression model. In addition, the effects of AD-related brain pathology detected in frontal cortical brain biopsies in iNPH patients’ cognitive profiles were examined.

Results:

The iNPH patients performed worse than cognitively healthy people in all CERAD-NB subtests. Despite similar performances in the MMSE, AD patients outperformed iNPH patients in Verbal Fluency (p = 0.016) and Clock Drawing (p < 0.001) tests. However, iNPH patients outperformed AD patients in the Boston Naming Test and Word List Recall and Recognition (p < 0.001). AD-related pathology in brain biopsies did not correlate with the CERAD-NB results.

Conclusion:

At the time of the iNPH diagnosis, cognitive performances differed from cognitively healthy people in all CERAD-NB subtests. When the iNPH and AD patients’ results were compared, the iNPH patients performed worse in Verbal Fluency and Clock Drawing tests while the AD group had more pronounced episodic memory dysfunctions. This study demonstrates significant differences in the CERAD-NB subtests between cognitive profiles of iNPH and AD patients. These differences are not captured by the MMSE alone.

Keywords

Alzheimer’s disease CERAD-NB Mini-Mental Status Examination neuropsychological test normal pressure hydrocephalus

INTRODUCTION

Idiopathic normal pressure hydrocephalus (iNPH) is a progressive neurodegenerative syndrome with distinctive symptom triad including impaired gait, cognitive decline, and urinary incontinence [1, 2]. Presumably iNPH is caused by abnormal cerebrospinal fluid (CSF) hydrodynamics [2, 3] which can be treated with CSF shunt surgery [4].

Previously reported iNPH-related cognitive symptoms are inattention, memory deficit, impaired executive functions, psychomotor slowing suggesting subcortical and frontal involvement and neuropsychiatric symptoms such as progressive apathy and lack of spontaneity [5 –10]. Thus, the neuropsychological performance of patients with iNPH differ substantially from healthy individuals and the preoperative neuropsychological deficits in iNPH are wide-ranging, interrelated, associated with neurological signs, and aggravated by vascular comorbidity [11]. iNPH patients characteristically have intact recognition memory, but deficits in recall and psychomotor speed [12]. However, in clinical setting the differential diagnosis between Alzheimer’s disease (AD) is challenging [7, 13]. Since full neuropsychological evaluation is rarely available, Mini-Mental State Examination (MMSE) [14] is often used to detect cognitive decline in iNPH although it is not considered sensitive enough to detect early cognitive impairment [15]. The Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB) is easy to perform and commonly used to measure cognitive impairment in patients with AD [16, 17]. However, the usefulness of CERAD-NB for describing the cognitive impairment in iNPH is unknown.

Neuropathological findings associated with AD have been reported in 62% of iNPH cases at autopsy [18, 19] and in up to 50% of living iNPH patients examined with brain biopsy [19]. Thus, the differential diagnostics between iNPH and AD can be challenging due to possible overlapping pathologies.

Here we aimed to differentiate iNPH from cognitively healthy aged persons and from mild AD using CERAD-NB. Furthermore, we compared CERAD-NB between iNPH patients with and without AD related neuropathology in frontal cortical brain biopsy in vivo.

MATERIALS AND METHODS

Between April 2009 and February 2015, data from 199 consecutive patients with suspected iNPH was collected in the Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland (Fig. 1).

Fig. 1

Patient selection flowchart. iNPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer’s disease; PD, Parkinson’s disease; MCI, mild cognitive impairment; VaD, vascular dementia; CERAD-NB, Consortium to Establish a Registry for Alzheimer’s Disease - Neuropsychological Battery.

The international iNPH diagnostic guidelines describe three different levels of diagnostic criteria: possible, probable, and unlikely [2]. Patients with possible iNPH have one or more typical clinical symptoms of iNPH including impaired gait, cognitive decline, or urinary incontinence. Patients with probable iNPH also present physiological evidence in support of the diagnosis [2]. All the iNPH patients in this study fulfilled diagnostic criteria of probable iNPH.

The patients with suspected iNPH were referred for further neurosurgical investigations if 2–3 symptoms possibly related to iNPH (impaired cognition with impaired gait or urinary incontinence) were present, accompanied by enlarged brain ventricles (Evan’s index > 0.30) disproportionate to the size of the sulci of the cerebral convexities on computed tomography (CT) or magnetic resonance imaging (MRI) [1]. A study neurologist specialized in memory disorders (ON and AMK) reviewed the iNPH patient cohort for a possible differential diagnosis. During this, the patients fulfilling the criteria of The National Institute on Aging and The Alzheimer’s Association for AD [20], the NINDS-AIREN diagnostic criteria for vascular dementia [21], or any other neurodegenerative disease or any disease (e.g., Parkinson’s disease) clearly explaining the patients’ symptoms better than iNPH, were excluded.

All the patients in the iNPH cohort were shunted. The patients were selected for shunting using ICP measurement results suggestive for iNPH until the end of year 2010. Since the beginning of 2011, a tap test was routinely performed and if the gait speed increased at least 20%, the patient was shunted. Furthermore, if the tap test was indecisive, the patients were shunted based on an abnormal lumbar CSF infusion using the Likvor CELDA^® system. Increased outflow resistance over 12 mmHg/ml/min was considered to support the diagnosis of probable iNPH [20, 21]. The treatment decision was made with ICP measurement for 32.7% (65/199) patients, with tap test for 43.2% (86/199) patients and with CSF infusion test for 23.6% (47/199) of the patients. One patient was shunted based on best clinical judgement without invasive measurements due to challenging patient co-operation. The brain biopsy pathology was not used as an excluding criterion for the iNPH cohort. The patients with secondary hydrocephalus were also excluded from the iNPH cohort. The detailed iNPH patient selection protocol used in Kuopio University Hospital for shunting has been described previously [22, 23].

The shunt response was evaluated clinically and since 2010 using iNPH Grading Scale (iNPHGS) and/or at least 20% increase in measured gait speed at 3 months follow up visit. The pre-shunt and 3-month iNPHGS data was available for 84.3% of the iNPH patients (167/199). A positive iNPHGS shunt response (decrease of ≥1 point) in 3 months follow up was reported in 46.7% of the patients (78/167). The data for gait speed in pre-shunt and 3 months control visit was available for 60.3% (120/199) patients. A positive shunt response described as gait speed increase at least 20% was reported with 57.5% of the patients (69/120). Data for subjective patient evaluation for a shunt response was available for 98.0% of the patients (195/199). Altogether 88.2% (172/195) of the patients reported a subjective positive shunt response with alleviation of at least 1/3 iNPH related symptoms reported by the patient (gait, memory or incontinence). In conclusion, altogether 89.4 % (178/199) of the iNPH patients reported a positive shunt response measured by at least one of these criterions.

For comparison, 236 patients adjusted for age and gender, with very mild or mild AD, with a clinical dementia rating (CDR) of 0.5 to 1, were derived from a Kuopio ALSOVA study, described in detail previously [24]. This cohort of patients were carefully examined previously and none of these patients fulfilled the diagnostic criteria for iNPH. A cohort of 309 healthy control subjects was used from a previously described CERAD-NB Finnish validation study [16].

Data availability

Anonymized data will be shared by reasonable request from any qualified investigator with material transfer agreement between Kuopio University Hospital and recipient institution.

Biopsy procedure and immunohistochemistry

During the CSF shunt procedure performed prior to the insertion of the ventricular catheter, 1–3 cylindrical cortical brain biopsies of 3–7 mm in length and 2–5 mm in diameter were obtained with biopsy forceps or needles. The biopsy site was approximately 3 cm from the midline and near to the coronal suture of the scalp. The details of the immunohistochemical analyses on the biopsies have been described previously [6, 25]. From all samples, a neuropathologist (TR) analyzed the cellular or the neuronal immunoreactivity for amyloid-β (Aβ) and hyperphosphorylated tau (HPτ) with light microscopy and the results were graded as present or absent. The patients were then further classified into groups by the presence of the pathology of Aβ and/or HPτ observed in the frontal cortical biopsies.

Cognitive evaluation

The CERAD-NB is derived from previously established cognitive tests [17]. The Finnish version of the CERAD-NB test battery includes nine subtests: Verbal Fluency (animals in 60 seconds), The 15-Item Boston Naming Test (scale of 0–15), the MMSE (scale of 0–30), Word List Learning (scale of 0–30), Word List Recall (scale of 0–10), Word List Recognition (%, scale of 0–100), Constructional Praxis (scale of 0–11), Delayed Constructional Praxis (scale of 0–11) and Clock Drawing (scale of 0–6) [16]. Furthermore, a Saving Score (%, scale of 0–100) was derived from the Word List tasks.

The CERAD-NB was performed before the shunting during a primary visit at the neurosurgical unit and was done by an experienced research nurse trained to perform the CERAD-NB.

As the common education in Finland lasts for 9 years, the patients were dichotomized according to the educational years to ≤9 years and > 9 years of education.

Statistical analysis

The data were analyzed with the Statistical Package for Social Sciences (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, New York, USA). The significance of the differences in the CERAD-NB and the clinical variables between the participants with iNPH, AD and the healthy controls were tested with the Pearson Chi-square test for the non-continuous variables. For the continuous variables, the Mann-Whitney U-test or the independent samples Kruskal Wallis test were used, respectively. Due to non-normal distribution Mann-Whitney U-test was used. The multivariate linear regression analysis was performed by using the enter-method for the prediction of each CERAD-NB subtest in each study subgroup. The multivariate analyses were adjusted for age, gender, and education. All tests for significance were two-sided, with probabilities of < 0.05 considered to be statistically significant. All the assumptions of the linear regression were met.

Ethical issues

The Kuopio University Hospital Research Ethical Committee, the Finnish National Supervisory Authority for Welfare and Health, and the Finnish Ministry of Social Affairs and Health approved this study as well as the original ALSOVA study and the Finnish CERAD-NB validation study. All subjects provided written informed consent to participate in the study.

RESULTS

The demographic data on the study populations and the CERAD subtest results are described in Tables 1 and 2. The patients with iNPH performed worse in all CERAD subtests than the general healthy population (Table 1). The patients with iNPH and AD were similar regarding age and gender. However, the iNPH group was more educated (p < 0.001) (Table 2). The differences in the CERAD-NB subtests between the healthy people, the iNPH patients and the AD patients are presented visually in Fig. 2. In the multivariate linear regression analyses, the MMSE and the Word List Learning results were similar between the iNPH and the AD groups (Table 3). The iNPH patients performed worse than the AD patients in the Verbal Fluency (p = 0.016) and the Clock Drawing (p < 0.001) tests. However, the iNPH patients performed better than the AD patients in the Boston Naming Test and the Word List Recall and Recognition (p < 0.001). The Constructional Praxis was worse in the patients with iNPH (p = 0.001), whereas the patients with AD tended to perform worse in the Delayed Constructional Praxis, but the differences were not statistically significant (p = 0.090) (Table 3). The neuropathological findings in the frontal cortical brain biopsies of 192 iNPH patients are described in Table 4. In the iNPH patients, the groups with and without AD-related pathology in the brain biopsies differed only by age and verbal fluency (Table 4). However, in the regression analysis adjusted for age, gender and education, the verbal fluency tended to deteriorate with increasing co-morbid AD-pathology in the brain biopsy but remained statistically insignificant (Tables 4 and 5).

Table 1

The comparison between the 508 study participants with iNPH and the healthy general population

Variables	199 iNPH			309 healthy controls			Comparisons
	Mean or N	SD or %	N	Mean or N	SD or %	N	Statistics¹	Cohen’s d	p
Characteristics
Age	74.8	6.5		71.6	4.1		17501.0		< 0.001
Education level (≤9 y)	[127]	65		[175]	57		3.3		0.077
Sex (Female)	[108]	54		[207]	67		8.3		0.005
CERAD-NB Subtests (Scale)
Verbal Fluency (animals in 60 s)	12.2	5.0		20.6	5.8	305	52447.5	1.528	< 0.001
15-Item Boston Naming Test (0–15 scale)	11.0	2.8		12.9	1.9	308	43399.0	0.828	< 0.001
Mini-Mental State Exam (MMSE, 0–30 scale)	22.1	4.8		27.5	1.7		53325.0	1.645	< 0.001
Word List Learning (0–30 scale)	13.3	4.8		19.8	3.6		53396.5	1.581	< 0.001
World List Recall (0–10 scale)	3.1	2.2	198	6.5	1.7		53974.5	1.779	< 0.001
World List Recall Savings % (0–100 scale)	52.6	34.4	197	83.5	15.4		46770.0	1.256	< 0.001
World List Recognition % (0–100 scale)	83.8	13.1	198	96.0	6.2		48651.5	1.283	< 0.001
Constructional Praxis (0–11 scale)	7.9	2.3	196	9.7	1.5	303	44156.0	0.970	< 0.001
Delayed Constructional Praxis (0–11 scale)	4.4	3.2	196	7.3	3.1	302	44064.5	0.924	< 0.001
Clock Drawing (0–6 scale)	3.2	2.0	198	5.2	1.1	303	46389.0	1.315	< 0.001

¹Sex and Education are Chi Square, and the rest are Mann-Whitney U. [N] The number of observations if any data missing. iNPH, idiopathic normal pressure hydrocephalus; CERAD-NB, Consortium to Establish a Registry for Alzheimer’s Disease –Neuropsychological Battery.

Table 2

The comparison between the 435 study participants with iNPH or AD, in the CERAD-NB subtests

Variables	199 iNPH patients			236 AD patients			Comparisons
	Mean or N	SD or %	N	Mean or N	SD or %	N	Mann-Whitney U	Cohen’s d	p
Characteristics
Age	75.0	6.5		75.0	6.5		24260.0		0.551
Education level (≤9 y)	[127]	65		193	82				< 0.001
Sex (Female)	[108]	54		121	51				0.564
CERAD-NB Subtests (Scale)
Verbal Fluency (animals in 60 s)	12.2	5.0		13.5	5.2		26635.0	0.254	0.016
15-Item Boston Naming Test (0–15 scale)	11.0	2.8		9.9	2.7		18201.0	0.401	< 0.001
Mini-Mental State Exam (MMSE, 0–30 scale)	22.1	4.8		21.5	3.4		20102.0	0.146	0.009
Word List Learning (0–30 scale)	13.3	4.8		12.3	3.9		19872.0	0.231	0.006
Word List Recall (0–10 scale)	3.1	2.2	198	2.1	1.8		17012.5	0.502	< 0.001
Word List Recall Savings % (0–100 scale)	52.6	34.4	197	41.1	32.4	235	18761.0	0.345	0.001
Word List Recognition % (0–100 scale)	83.8	13.1	198	77.6	13.9	235	16964.0	0.458	< 0.001
Constructional Praxis (0–11 scale)	7.9	2.3	196	8.4	1.9	235	25497.0	0.239	0.050
Delayed Constructional Praxis (0–11 scale)	4.4	3.2	196	3.5	3.0	235	19467.0	0.291	0.005
Clock Drawing (0–6 scale)	3.2	2.0	198	4.0	1.7	235	28355.5	0.434	< 0.001

[N] The number of participants if any data missing. iNPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer’s disease; CERAD-NB, Consortium to Establish a Registry for Alzheimer’s Disease –Neuropsychological Battery.

Fig. 2

Comparison between iNPH and AD variables in the CERAD-NB. Data is derived from Tables 1 and 2 and reconstructed as percentage of maximum scale on each subtest (0–100%). iNPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer’s disease; CERAD-NB, Consortium to Establish a Registry for Alzheimer’s Disease –Neuropsychological Battery. ^*For demonstration purposes a cap of 24 was placed on Verbal Fluency, which represents 1 SD above the normal aging population mean [16].

Table 3

Linear regression model adjusted for age, sex, diagnosis and education for the prediction of each CERAD-NB subtest

CERAD -NB Subtests	Predictors in the regression model	Unstandardized coefficient B	95% CI for B	p	t	R²	F	Collinearity diagnostics
								Tolerance	Variance inflation factor
Verbal Fluency (animals in 60 s) [432]	Age	–0.05	–0.13 –0.02	0.163	–1.40			0.96	1.05
	Sex (female = 1, otherwise 0)	–0.57	–1.52–0.37	0.233	–1.20			0.99	1.00
	Diagnosis (0 = iNPH,1 = AD)	1.77	0.81–2.73	< 0.001	3.62			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	2.37	1.25–3.48	< 0.001	4.18			0.93	1.08
	Regression model			< 0.001		0.07	7.80
15-Item Boston Naming Test (0–15 scale) [432]	Age	–0.07	–0.11––0.04	< 0.001	–3.82			0.96	1.05
	Sex (female = 1, otherwise 0)	1.20	0.72–1.68	< 0.001	4.90			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	–0.82	–1.31––0.33	0.001	–3.31			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	1.59	1.03–2.16	< 0.001	5.53			0.93	1.08
	Regression model			< 0.001		0.19	25.91
Mini-Mental State Exam (MMSE, 0–30 scale) [432]	Age	–0.04	–1.01–0.01	0.135	–0.07			0.96	1.05
	Sex (female = 1, otherwise 0)	0.10	–0.63–0.84	0.782	0.28			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	–0.14	–0.86–0.61	0.716	–0.36			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	3.14	2.28–4.01	< 0.001	7.14			0.93	1.08
	Regression model			< 0.001		0.13	15.80
Word List Learning (0–30 scale) [432]	Age	–0.05	–0.11–0.01	0.134	–1.50			0.96	1.05
	Sex (female = 1, otherwise 0)	–1.29	–2.06––0.51	0.001	–3.27			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	–0.47	–1.26–0.32	0.245	–1.16			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	2.68	1.77–3.60	< 0.001	5.77			0.93	1.08
	Regression model			< 0.001		0.12	13.88
World List Recall (0–10 scale) [431]	Age	–0.01	–0.04–0.02	0.520	–0.64			0.96	1.05
	Sex (female = 1, otherwise 0)	0.01	–0.35–0.37	0.965	0.04			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	–0.79	–1.16––0.42	< 0.001	–4.21			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	1.19	0.76–1.62	< 0.001	5.47			0.93	1.08
	Regression model			< 0.001		0.13	15.50
World List Recall savings % (0–100 scale) [429]	Age	–0.04	–0.53–0.46	0.878	–0.15			0.95	1.05
	Sex (female = 1, otherwise 0)	5.34	–0.97–11.64	0.097	1.66			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	–9.96	–16.39––3.54	0.002	–3.05			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	9.83	2.38–17.28	0.010	2.59			0.93	1.08
	Regression model			< 0.001		0.05	5.76
World List recognition % (0–100 scale) [430]	Age	–0.20	–0.40––0.00	0.049	–1.97			0.96	1.05
	Sex (female = 1, otherwise 0)	0.35	–2.17–2.88	0.782	0.275			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	–5.21	–7.78––2.64	< 0.001	–3.98			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	5.72	2.75–8.70	< 0.001	3.78			0.93	1.08
	Regression model			< 0.001		0.10	11.46
Constructional praxis (0–11 scale) [428]	Age	–0.01	–0.04–0.02	0.596	–0.53			0.95	1.05
	Sex (female = 1, otherwise 0)	0.14	–0.23–0.51	0.464	0.734			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	0.67	0.29–1.05	0.001	3.46			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	1.42	0.98–1.86	< 0.001	6.33			0.92	1.08
	Regression model			< 0.001		0.11	12.38
Delayed Constructional praxis (0–100) [428]	Age	–0.03	–0.08–0.01	0.131	–1.51			0.95	1.05
	Sex (female = 1, otherwise 0)	0.00	–0.56–0.56	0.999	–0.00			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	–0.47	–1.07–0.08	0.090	–1.70			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	2.04	1.38–2.71	< 0.001	6.01			0.92	1.08
	Regression model			< 0.001		0.11	13.25
Clock Drawing (0–6 scale) [430]	Age	–0.02	–0.05–0.01	0.177	–1.35			0.95	1.05
	Sex (female = 1, otherwise 0)	–0.16	–0.51–0.19	0.366	–0.91			0.99	1.01
	Diagnosis (0 = iNPH,1 = AD)	0.89	0.54–1.25	< 0.001	4.91			0.96	1.04
	Nine years or less of acquired education (= 1, otherwise 2)	0.70	0.29–1.12	0.001	3.32			0.93	1.08
	Regression model			< 0.001		0.07	8.53

The number of cases included in the regression model. CERAD-NB, Consortium to Establish a Registry for Alzheimer’s Disease –Neuropsychological Battery; iNPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer’s disease.

Table 4

The pathological profile in the frontal cortical biopsies of the 192 iNPH patients¹

	Findings in the frontal cortical biopsies										Comparisons
Variables	Aβ−, HPτ−			Aβ+, HPτ−		Aβ+, HPτ+			Aβ−, HPτ+		Statistics^a	Independent samples, Kruskal Wallis test
	[n = 83]			[n = 72]		[n = 33]			[n = 4] Excluded from the comparisons
	Mean	SD or %	N	Mean	SD or %	Mean	SD or %	N	Mean	SD or %		p
Characteristics
Age	72.2	6.8		76.1	5.7	78.3	4.5		76.0	6.5	26.08	< 0.001²
Education level (≤9 y)	[51]	62	[82]	[45]	63	[23]	70	[31]	2	50	χ² = 3.25	0.197
Sex (Female)	[40]	48		[39]	54	[22]	67		3	75	χ² = 1.58	0.453
The CERAD-NB Subtests (Scale)
Verbal Fluency (animals in 60 s)	12.9	4.8		12.1	5.0	10.3	4.3		15.8	9.1	7.06	0.029³
15-Item Boston Naming Test (0–15 scale)	11.2	2.8		11.2	2.7	10.1	2.7		11.3	4.9	4.82	0.090
Mini-Mental State Exam (MMSE, 0–30 scale)	22.7	4.4		22.1	5.1	20.7	5.1		22.8	7.8	3.38	0.185
Word List Learning (0–30 scale)	13.2	4.4		14.1	5.0	11.8	4.1		14.8	10.5	5.13	0.077
World List Recall (0–10 scale)	3.1	1.9		3.2	2.4	2.6	2.1	[32]	4.3	3.4	1.85	0.397
World List Recall Savings % (0–100 scale)	55.3	32.8	[82]	49.6	35.1	51.6	39.0	[32]	56.4	39.3	1.04	0.569
World List Recognition % (0–100 scale)	84.6	11.6	[82]	85.9	12.5	78.8	16.3	[32]	81.3	21.4	4.70	0.095
Constructional Praxis (0–11 scale)	8.2	2.2	[81]	7.8	2.1	7.8	2.6	[32]	9.0	1.8	1.72	0.424
Delayed Constructional Praxis (0–100)	4.9	3.3	[82]	4.1	3.1	4.1	3.5	[32]	4.0	3.6	2.72	0.257
Clock Drawing (0–6 scale)	3.4	2.1		3.1	2.1	3.1	2.0	[32]	3.0	1.6	1.06	0.588

^aEducation level and sex are Pearson Chi-Square, the rest are Mann-Whitney U, [] The number of participants. ¹In 7 patients the biopsy or the staining was unsuccessful. ²In pairwise comparisons, the people with the absence of the Aβ and the HPτ pathology in the frontal cortical biopsy were significantly different from those presenting either one (Aβ+, HPτ - or Aβ+, HPτ+). ³In pairwise comparisons the people with the absent Aβ and HPτ pathology in the frontal cortical biopsy were significantly different from those presenting both Aβ and HPτ. Aβ, amyloid-β; HPτ, hyperphosphorylated tau; CERAD-NB, Consortium to Establish a Registry for Alzheimer’s Disease –Neuropsychological Battery; iNPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer’s disease.

Table 5

Linear regression model adjusted for age, sex, brain biopsy and education for the prediction of each CERAD-NB subtest in the iNPH patients

CERAD -NB Subtests	Predictors in the regression model	Unstandardized coefficient B	95% CI for B	p	t	R²	F	Collinearity diagnostics
								Tolerance	Variance inflation factor
Verbal Fluency (animals in 60 s) [n = 185]	Age	– 0.04	– 0.15– 0.08	0.534	– 0.624			0.83	1.21
	Sex (female = 1, otherwise 0)	– 1.66	– 3.01– – 0.31	0.016	– 2.43			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	1.38	– 0.05– 2.82	0.058	1.91			0.87	1.15
	Nine years or less of acquired education (= 1, otherwise 2)	2.96	1.54– 4.38	<0.001	4.12			0.95	1.05
	Regression model			<0.001		0.14	7.17
15-Item Boston Naming Test (0– 15 scale) [n = 185]	Age	– 0.07	– 0.13– – 0.01	0.028	– 2.22			0.83	1.21
	Sex (female = 1, otherwise 0)	1.19	0.45– 1.94	0.002	3.17			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	– 0.10	– 0.89– 0.69	0.808	– 0.24			0.87	1.15
	Nine years or less of acquired education (= 1, otherwise 2)	1.59	0.81– 2.38	<0.001	4.01			0.95	1.05
	Regression model			<0.001		0.18	10.12
Mini-Mental State Exam (MMSE, 0– 30 scale) [n = 185]	Age	– 0.10	– 0.21– 0.01	0.081	– 1.75			0.83	1.21
	Sex (female = 1, otherwise 0)	– 0.52	– 1.82– 0.79	0.436	– 0.78			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	0.52	– 0.87– 1.90	0.463	0.74			0.87	1.15
	Nine years or less of acquired education (= 1, otherwise 2)	3.52	2.15– 4.89	<0.001	5.06			0.95	1.05
	Regression model			<0.001		0.17	9.12
Word List Learning (0– 30 scale) [n = 185]	Age	– 0.11	– 0.21– 0.00	0.052	– 1.96			0.83	1.21
	Sex (female = 1, otherwise 0)	– 1.59	– 2.87– – 0.31	0.015	– 2.46			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	– 0.59	– 1.95– 0.77	0.391	– 0.86			0.87	1.15
	Nine years or less of acquired education (= 1, otherwise 2)	3.12	1.77– 4.47	<0.001	4.57			0.95	1.05
	Regression model			<0.001		0.16	8.46
World List Recall (0– 10 scale) [n = 184]	Age	– 0.04	– 0.09– 0.01	0.117	– 1.58			0.83	1.21
	Sex (female = 1, otherwise 0)	– 0.48	– 1.08– 0.12	0.116	– 1.58			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	– 0.122	– 0.76– 0.51	0.704	– 0.38			0.88	1.14
	Nine years or less of acquired education (= 1, otherwise 2)	1.38	0.75– 2.01	<0.001	4.30			0.95	1.05
	Regression model			<0.001		0.13	6.64
World List Recall savings % (0– 100 scale) [n = 183]	Age	(– 0.15)	(– 1.00– 0.70)	(0.723)	(– 0.36)			(0.83)	(1.21)
	Sex (female = 1, otherwise 0)	(– 1.15)	(– 11.37– 9.06)	(0.824)	(– 0.22)			(0.97)	(1.03)
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	(4.33)	(– 6.45– 15.10)	(0.429)	(0.79)			(0.88)	(1.14)
	Nine years or less of acquired education (= 1, otherwise 2)	(12.97)	(2.21– 23.73)	(0.018)	(2.38)			(0.95)	(1.05)
	Regression model			(0.111)		(0.04)	(1.91)
World List recognition % (0– 100 scale) [n = 184]	Age	– 0.44	– 0.74– – 0.13	0.006	– 2.81			0.83	1.21
	Sex (female = 1, otherwise 0)	– 2.21	– 5.90– 1.47	0.238	– 1.19			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	– 1.06	– 4.96– 2.84	0.592	– 0.54			0.88	1.14
	Nine years or less of acquired education (= 1, otherwise 2)	6.15	2.28– 10.03	0.002	3.14			0.95	1.05
	Regression model			<0.001		0.12	5.79
Constructional praxis (0– 11 scale) [n = 182]	Age	– 0.05	– 0.10– 0.00	0.058	– 1.91			0.83	1.21
	Sex (female = 1, otherwise 0)	– 0.01	– 0.64– 0.63	0.988	– 0.02			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	0.14	– 0.52– 0.81	0.678	0.42			0.88	1.14
	Nine years or less of acquired education (= 1, otherwise 2)	1.48	0.81– 2.14	<0.001	4.39			0.95	1.06
	Regression model			<0.001		0.15	7.52
Delayed Constructional praxis (0– 100) [n = 183]	Age	– 0.09	– 0.17– – 0.02	0.013	– 2.50			0.83	1.21
	Sex (female = 1, otherwise 0)	– 0.29	– 1.18– 0.60	0.517	– 0.65			0.97	1.03
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	0.41	– 0.53– 1.35	0.392	0.86			0.88	1.14
	Nine years or less of acquired education (= 1, otherwise 2)	1.92	0.99– 2.86	<0.001	4.05			0.95	1.05
	Regression model			<0.001		0.15	8.11
Clock Drawing (0– 6 scale) [n = 184]	Age	– 0.05	– 0.10– – 0.00	0.046	– 2.01			0.83	1.21
	Sex (female = 1, otherwise 0)	– 0.39	– 0.98– 0.21	0.200	– 1.29			0.97	1.14
	Absence of both Aβ and HPτ (1 = yes, 0 = no)	0.14	– 0.49– 0.76	0.670	0.43			0.88	1.14
	Nine years or less of acquired education (= 1, otherwise 2)	0.74	0.12– 1.37	0.019	2.36			0.95	1.05
	Regression model			0.007		0.08	3.62

() Statistically insignificant regression model. CERAD-NB, Consortium to Establish a Registry for Alzheimer’s Disease – Neuropsychological Battery; iNPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer’s disease.

DISCUSSION

The most important novel findings of this study were 1) the CERAD-NB subtests show significant differences between the patients with iNPH and AD that are not captured by the MMSE alone and therefore the MMSE cannot be reliably used in differentiating iNPH from AD, 2) the iNPH patients performed worse than the AD patients in the Verbal Fluency and Clock Drawing tests, 3) the AD patients had more pronounced episodic memory impairment, and 4) the brain biopsy pathology related to AD did not explain the CERAD-NB subtests results.

The differential diagnostics within the neuropsychological profile of iNPH have been explored previously in smaller cohorts [5–12 , 26–28]. Our findings align with the previous observations as the frontal lobe dysfunction has been reported to be the primary cognitive symptom in iNPH [11, 27]. Similarly, with our findings, Saito et al. (2011) found no difference in the MMSE between the iNPH and the AD groups. Furthermore, they reported worse performances in the iNPH group in tests assessing the executive functions such as Spatial Span, Phoneme Fluency, Trail Making Test A, and Frontal Assessment Battery when compared to the patients with AD and the healthy controls. Additionally, episodic memory impairment was more pronounced in the patients with AD than in the patients with iNPH [27].

Our results indicate that the MMSE cannot be reliably used in differentiating iNPH from AD. Our findings demonstrate the superiority of the CERAD-NB subtests when compared with the MMSE in the early recognition of cognitive impairment in iNPH. Furthermore, the CERAD-NB subtest provide more detailed information regarding other differential diagnostics, such as frontotemporal lobe degeneration [29]. The CERAD-NB is relatively easy to perform and can be used in a clinical setting differentiating the normal, cognitively healthy people from those with iNPH. As our finding suggests, when deficits in Verbal Fluency and Clock Drawing tests are more pronounced, the CERAD-NB can be used as a supportive tool for diagnosing iNPH. However, when there is more pronounced episodic memory dysfunction, further investigations are needed.

iNPH itself presents a clinical diagnostic challenge, since the co-morbidities related to other neurodegenerative diseases are common [7, 30]. Our findings in the frontal cortical brain biopsies support that AD-related pathology is common in the iNPH patients, but it does not cause distinct differences in the CERAD-NB subtests. We found AD-related pathology in 54.7% of our iNPH patients’ frontal cortical brain biopsies, which is well-aligned with the previous reports indicating multiple confounding co-morbidities [18, 19]. As the CSF biomarkers for AD correlate with the cortical brain biopsy findings [25], our results suggest that the lumbar CSF AD biomarkers cannot solely be reliably used in differentiating iNPH from AD as suggested previously [31].

Based on extensive literature search, we have so far one of the largest cohorts with detailed characteristics of the cognitive tests in iNPH. Additionally, the AD cohort of the ALSOVA study and the healthy controls have been carefully examined as reported earlier [15, 16]. To our knowledge, this was the first time when the cognition of iNPH assessed with the CERAD-NB was examined.

This study also has some limitations. The cognitive evaluations were not done with full neuropsychological evaluation, but the CERAD-NB is easy, fast, widely used and validated the measure of the cognitive impairment in the patients with AD and also studied in other neurodegenerative disorders [16 , 29]. We acknowledge the possible confounding factors of co-morbidity in iNPH. However, the patient selection was done using probable iNPH criteria during the first diagnostic work up, and further follow-up of these patients would increase the accuracy of the differential diagnostics. Also, it is important to recognize that the statistical analyses presented in this study, compare the performance of the different groups in the subtests applied, but they do not allow to establish cognitive profiles of the participants in each group, since this would require a more comprehensive neuropsychological evaluation.

Based on the previous studies, symptoms of depression are more common in iNPH population than in the normal elderly population, and existing depression may mimic or worsen the cognitive symptoms of iNPH [32]. Unfortunately, in our study population we have systematically collected the depression data only since 2011 with Beck Depression Inventory (BDI-II) [33] prior to shunt surgery. In this study, the BDI-II data was available for 83 of the 199 iNPH patients (41.7%). Based on BDI-II grading, altogether 21.7% (18/83) reported mild depression (BDI-II scale 14–19), 13.3% (11/83) reported moderate depression (BDI-II scale 20–28), and 4.8% (4/83) reported severe depression (BDI-II scale 29–63). We did not find any significant correlation between BDI-II score and any CERAD-NB subtests (r = –0.120––0.054, p > 0.1 for all subtests) in the iNPH patient group.

Since the brain biopsy represents only a small region in the frontal cortex, false negative results on tau-pathology can be expected. However, biopsy can be used to detect Aβ aggregates in the frontal cortex which correlates well with the whole brain Aβ pathology [19].

As the statistical differences of CERAD-NB results between iNPH and AD are minimal, it is important to recognize that the usefulness and significance of these findings in clinical differential diagnostics is limited. However, based on this study, CERAD-NB is more sensitive than MMSE to detect cognitive deterioration in iNPH patients and can easily be used in the clinical practice.

Future perspectives

Further investigations in reaching a simple and effective way of reliably diagnosing iNPH preoperatively are still warranted. Furthermore, we should have better methods to estimate which iNPH patients will benefit from shunting especially regarding cognition. Improvements or changes of the cognition in iNPH after the shunting should be investigated.

As the Montreal Cognitive Assessment (MoCA) is widely used instead of MMSE in the clinical setting, it also would be interesting to explore the usefulness of MoCA to screen cognitive deterioration in a larger cohort of iNPH patients. According to a literature search, the characteristics of cognitive function evaluation using the MoCA with idiopathic normal pressure hydrocephalus has only been evaluated in a small study of 32 patients [34].

Since iNPH seems to present with cognitive symptoms suggesting subcortical and frontal involvement [5 –10], it would be interesting to compare the neuropsychology of iNPH to other neurodegenerative diseases with decline in the executive functions, psychomotor slowness, behavioral and personality changes with ventricular enlargement, especially behavioral variant frontotemporal dementia [29, 35]. Additionally, vascular cognitive impairment and memory disorders with pathology related to the Lewy body, such as dementia with the Lewy bodies, multisystem atrophy, or Parkinson’s disease should be considered for the differential diagnosis (Fig. 1). Furthermore, people with rare tauopathies such as progressive supranuclear palsy and corticobasal degeneration may imitate the cognitive and other neurological symptoms of iNPH. The potential usefulness of the CERAD-NB in these disorders would be interesting to explore in a clinical setting [36].

In conclusion, this study indicates that within the CERAD-NB subtests, deficits in Verbal Fluency and Clock Drawing tests are more pronounced in the iNPH patients and episodic memory dysfunction in the AD patients. The CERAD-NB is more reliable in differentiating the cognitive dysfunctions between the iNPH patients and the healthy individuals when compared to the MMSE only. Additionally, solely MMSE cannot be reliably used in differentiating iNPH from AD. Also, AD-related brain pathology is common in iNPH patients, but it does not explain the CERAD-NB subtests results.

Footnotes

ACKNOWLEDGMENTS

We acknowledge RN Marita Parviainen for maintaining the iNPH registry and performing the CERAD-NB battery for the iNPH patients. We thank biostatistician Tuomas Selander for help with statistical issues.

This work was supported by Academy of Finland (grant number 307866); Sigrid Jusélius Foundation; the Strategic Neuroscience Funding of the University of Eastern Finland; Suomen Aivosäätiö and Finnish Cultural Foundation - North Savo Regional Fund.

Authors’ disclosures available online ().

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