Counting-backward test for executive function in idiopathic normal pressure hydrocephalus

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1 Acta Neurol Scand 2012: 126: DOI: /j x Ó 2012 John Wiley & Sons A/S ACTA NEUROLOGICA SCANDINAVICA Counting-backward test for executive function in idiopathic normal pressure hydrocephalus Kanno S, Saito M, Hayashi A, Uchiyama M, Hiraoka K, Nishio Y, Hisanaga K, Mori E. Counting-backward test for executive function in idiopathic normal pressure hydrocephalus. Acta Neurol Scand: 2012: 126: John Wiley & Sons A/S. Objectives The aim of this study was to develop and validate a bedside test for executive function in patients with idiopathic normal pressure hydrocephalus (INPH). Materials and Methods Twenty consecutive patients with INPH and 20 patients with Alzheimer s disease (AD) were enrolled in this study. We developed the countingbackward test for evaluating executive function in patients with INPH. Two indices that are considered to be reflective of the attention deficits and response suppression underlying executive dysfunction in INPH were calculated: the first-error score and the reverse-effect index. Performance on both the counting-backward test and standard neuropsychological tests for executive function was assessed in INPH and AD patients. Results The first-error score, reverse-effect index and the scores from the standard neuropsychological tests for executive function were significantly lower for individuals in the INPH group than in the AD group. The two indices for the counting-backward test in the INPH group were strongly correlated with the total scores for Frontal Assessment Battery and Phonemic Verbal Fluency. The first-error score was also significantly correlated with the error rate of the Stroop colour-word test and the score of the go/no-go test. In addition, we found that the first-error score highly distinguished patients with INPH from those with AD using these tests. Conclusion The counting-backward test is useful for evaluating executive dysfunction in INPH and for differentiating between INPH and AD patients. In particular, the first-error score may reflect deficits in the response suppression related to executive dysfunction in INPH. S. Kanno 1, M. Saito 1, A. Hayashi 1, M. Uchiyama 1, K. Hiraoka 1, Y. Nishio 1, K. Hisanaga 2, E. Mori 1 1 Department of Behavioural Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan; 2 Department of Neurology, Miyagi National Hospital, Watari, Miyagi Japan Key words: Alzheimer's disease; executive function; idiopathic normal pressure hydrocephalus; neuropsychological tests; response suppression S. Kanno, Department of Behavioural Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi , Japan Tel.: Fax: s-kanno@med.tohoku.ac.jp Accepted for publication January 2, 2012 Introduction Normal pressure hydrocephalus (NPH) is a syndrome characterized by the clinical triad of gait disturbance, cognitive impairment and urinary incontinence and is associated with ventricular dilation and normal cerebrospinal fluid (CSF) pressure (1). By definition, idiopathic NPH (INPH) carries no causative antecedent disease, such as subarachnoid haemorrhages, meningitis or brain tumours. From recent cohort studies conducted in Japan, the prevalence of individuals with INPH, according to the magnetic resonance imaging (MRI) criteria of the Japanese Guidelines for INPH (2), was between 0.51% and 2.9% (3 5). With the increase in the proportion of elderly individuals in Japan, the detection and diagnosis of INPH have become increasingly important, particularly because INPH has been shown to be treatable with shunt placement. In contrast, Alzheimer s disease (AD) has been reported to be a common illness associated with dementia that often conflicts with the diagnosis and shunt responsiveness of patients with INPH (6, 7). Therefore, differentiating between INPH and AD is crucial for dementia screening. 279

2 Kanno et al. It has also been reported that a characteristic feature of cognitive impairment in patients with INPH is a deficit in executive function (8). One recent study demonstrated the effectiveness of using neuropsychological examinations to distinguish between patients with INPH and those with AD (9). However, in our experience, patients with INPH cannot tolerate complicated and lengthy exams, such as the Wisconsin Card Sorting Test (WCST) (10) or the Wechsler Adult Intelligence Scale (WAIS) (11), in a clinical setting. Therefore, a simple and useful neuropsychological assessment tool for evaluating executive function in patients with INPH is needed. Caplan (12) reported that aboulic patients with hydrocephalus had difficulty counting backwards from 20 to 1, despite having successfully counted forwards from 1 to 20. Counting backwards is thought to be a simple mental tracking task, which requires the subject to hold information regarding a tracking number in mind while subsequently reversing the order of a set of numbers. This task is associated with working memory, as well as the ability to focus and sustain attention (13). Response suppression is the ability to inhibit an incorrect response when also required to withhold responses to specific stimuli, such as those during the go/no-go test (14). The failure to count backward is likely caused by an intrusion of inappropriate routine schema (e.g. the process of counting forward), as the process of counting forward is more acquired and automatic than that of counting backward. Therefore, we hypothesized that the performance of this simple task, which reflects attention, working memory, and response suppression related to executive function, is defective in patients with INPH. The aim of this study was to develop the countingbackward test as a simple tool for quantitatively evaluating executive function in patients with INPH. We validated this test by evaluating its reliability and concurrent validity, and by examining its diagnostic value regarding the ability to differentiate INPH from AD. Methods This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by Tohoku University. Patients with INPH Thirty-four consecutive patients with INPH who underwent shunt surgery at Tohoku University Hospital between March 2007 and April 2009 were enrolled in this study. The patients were diagnosed with probable INPH by board-certified neurologists based on the diagnostic criteria established according to the Japanese Clinical Guidelines for INPH (2). The criteria for probable INPH are as follows: (i) >60 years of age; (ii) gait disturbance, dementia, and/or urinary incontinence; (iii) ventricular dilation (Evans Index > 0.3) with a narrow CSF space in the superior convexity; (iv) CSF pressure < 200 mm H 2 O with normal CSF cell counts and protein levels; (v) the absence of other diseases that may account for such symptoms; (vi) the lack of a previous history of illness that may cause ventricular dilation; and (7) a positive CSF tap test. Post-operatively, the patients were followed at the outpatient clinic, and the pressure setting of their programmable valve was adjusted in a stepwise manner. Pressure adjustments were made repeatedly until the optimal pressure for each patient was attained. Twenty-seven of the initial patients with INPH showed significant shunt responsiveness, which is defined as an improvement by one or more points on the idiopathic Normal Pressure Hydrocephalus Grading Scale (inphgs) within 1 year of shunt placement (15). However, patients who were unable to complete all the neuropsychological tests for clinical reasons, such as refusal of the examination, delirium or severe aboulia, were excluded from the study. Consequently, 20 patients with INPH were included in the study (Table 1). Of these patients, 17 patients (eight women and nine men) were re-evaluated approximately 1 year after shunt surgery (Table 2). The remaining three patients withdrew from the study for reasons including subdural haemorrhaging, lung cancer and residential relocation. In this study, clinical measures were assessed prior to performing both CSF removal and shunt placement, and were used to elucidate the neuropsychological features of the patients with preoperative INPH whose symptoms improved after shunt placement. Patients with AD Patients with AD were prospectively recruited from Tohoku University Hospital and Miyagi National Hospital from December 2006 to March Diagnoses were made by board-certified neurologists. The inclusion criteria for AD were as follows: (i) fulfilment of the criteria for probable AD according to the National Institute of Neurological and Communicative Disorders and the Stroke/AD and Related Disorders Association (16); (ii) lack of complications of other neurological 280

3 The counting-backward test for executive function in INPH Table 1 Demographic and clinical characteristics of the patients with INPH and AD Variables INPH (n = 20) AD (n = 20) P-value a Age in years, mean (SD) 75.5 (5.0) 77.6 (5.5) Sex, female/male 9/11 10/ Education years, mean (SD) 10.7 (4.0) 10.2 (2.5) MMSE, mean (SD) 22.4 (3.8) 22.7 (3.2) Total score: 30 ADAS word recall, mean (SD) 14.5 (4.3) 14.4 (3.5) Total score: 30 ADAS word recognition, mean (SD) 25.9 (8.3) 28.3 (7.3) Total score: 36 CSF shunt operation (VP/LP) 15/5 INPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer's disease; MMSE, Mini-Mental State Examination; ADAS, Alzheimer's Disease Assessment Scale; SD, standard deviation; VP, ventriculoperitoneal; LP, lumboperitoneal; CSF, cerebrospinal fluid. a Student's t-test was used except for sex ratio (Chi-square test). Table 2 Results of inphgs at baseline and 1 year after shunt surgery Variables diseases; and (iii) no demonstration of focal brain lesions on a cranial MRI. All patients with AD were given standard neuropsychological tests, including memory tests, cranial MRIs and single photon emission computer tomography (SPECT). All the clinical data were documented in the dementia registry. In this study, patients with AD were selectively and individually matched with patients with INPH based on age and the severity of cognitive dysfunction [as assessed by the Mini-Mental State Examination (MMSE) score] (17). The difference in age between each pair of patients was <5 years, and the difference in the MMSE score was <3 points. The INPH and AD groups did not differ significantly in terms of age, sex, educational attainment, scores on the MMSE, or scores for word recall and word recognition subtests from the AD Assessment Scale (ADAS) (18) (Table 1). The counting-backward test INPH (n = 20) Baseline INPH (n = 17) Post-operation P-value a INPHGS, median (range) Gait disturbance 2.0 (2 3) 2.0 (0 3) 0.006** Cognitive disturbance 3.0 (0 3) 2.0 (0 3) 0.011* Urinary disturbance 2.0 (0 3) 0.0 (0 2) 0.004** Total 6.5 (2 9) 4.0 (1 7) 0.001** INPH, idiopathic normal pressure hydrocephalus; inphgs, idiopathic normal pressure hydrocephalus grading scale. * P < 0.05; ** P < a Wilcoxon signed rank test was used. For the procedure of this test, each subject was first asked to count backward from 20 to 1 as quickly as possible (four trials). The patient s task completion time was measured for each trial using a handheld stopwatch, and the first incorrect number of the series was recorded for each trial (e.g. if the subject said 20, 19, 18, 17, 16, 14 1, the recorded number would be 15). The subject had approximately 10 s to state a numerical answer. In the event that the patient could not produce an answer or gave up counting backwards during a session, the trial was aborted and the number was recorded in the same way as described previously. For example, if the subject gave up counting backwards halfway through the trial, the last number that the subject could not produce was recorded (e.g. if the subject said 20, 19, 18, 17, and subsequently stopped, the recorded number would be 16). Next, the subjects were asked to count forwards from 1 to 20 as quickly as possible (four trials), and the completion time was recorded for each trial. We recorded the completion time only if the subject could say all the numbers (it did not matter whether the subject repeated a number while counting backwards or forwards). This test yielded two indices: the first-error score, which is an average of the first-error numbers of the four trials, and the reverse-effect index, which is the minimum completion time of the counting-backward trial minus the minimum completion time of the counting-forward trial. We assumed that the first-error score and the reverse-effect index reflected deficits of attention, working memory and response suppression in patients with INPH. Standard neuropsychological tests for executive function We administered a series of standard neuropsychological tests for executive function, including the Frontal Assessment Battery (FAB) (19), the phonemic verbal fluency test (PVF) (20), the Stroop colour-word test (SCWT) (21, 22), and the digit span (DS) subtest from the Wechsler Memory Scale-Revised (WMS-R) (23). The FAB is a simple and well-established battery test for assessing frontal lobe function. There are six subtests that assess the following aspects: (i) conceptualization and abstract reasoning (similarities); (ii) mental flexibility (phonemic verbal fluency); (iii) motor programming and executive control of action (Luria motor sequences); (iv) resistance to interference (conflicting instructions); (v) self-regulation and inhibitory control (go/no-go test); and (vi) environmental autonomy (prehensive behaviour). Each subtest is scored from 0 to

4 Kanno et al. The PVF, which is a separate test from the FAB and the phonemic verbal fluency subtest, is one of the most frequently used measures of executive function and is thought to be linked to response initiation (24). The subject is required to say as many words as possible within 60 s, and each subject needed to begin with the Japanese letters; Fu, A or Ni. We used the total number of words produced as the PVF score. The SCWT is also one of the most extensively studied measures of attention or response suppression associated with executive function (20). This test consists of three sets of stimuli: (i) the colour names (red, blue or yellow) printed in black ink, which required patients to read the response aloud; (ii) the colour of rectangles filled with red, blue or yellow ink, which required patients to name the response; and (iii) the colour of the ink in which the name of an incongruous colour is printed, which required patients to name the response. Each set consists of 30 stimuli. The subject was required to perform each set as quickly as possible. We recorded the error responses for each set, and the error rate of the third set was calculated as the index of the deficit of the suppressed response (the SCWT score). The DS test is a simple measure of attention and working memory. The forward span is more closely related to the efficiency of attention, whereas the backward span is the simplest test of mental tracking and is associated with verbal working memory (13). To evaluate the test retest reliability and the learning effect of each test in patients with INPH, each of the tests, including the counting-backward test, was repeated within an interval of 2 or 3 days (before both CSF removal and shunt placement). We used scores from the initial attempts for validation purposes. Statistical analyses The intrasubject reproducibility of the first-error score, reverse-effect index, and the total FAB, PVF, SCWT and DS scores (forward and backward), as expressed by the intraclass correlation coefficient (ICC), were calculated and later compared among the tests. In addition, we evaluated the learning effect of each test using the Wilcoxon signed rank test. The group differences that were observed regarding first-error scores, reverse-effect indices, and the total and subtest scores from the FAB, PVF, SCWT and DS (forward and backward) were examined using the Mann Whitney U-test. Spearman s rank correlation coefficient was used to identify potential associations between performance on the counting-backward test and performance on the standard neuropsychological tests for each group. In addition, a logistic regression analysis with a backward stepwise selection was performed to identify the best predictor for the differentiation between INPH and AD. To determine the cut-off score for the best predictor that would yield the highest sensitivity and specificity for this differentiation, a receiver operating characteristic (ROC) curve was used. Statistical analyses were performed using IBM SPSS statistics software (version 19.00; IBM SPSS Inc., Armonk, NY, USA), and the statistical significance was defined for P values < No correction for multiple comparisons was performed because of a priori hypothesis testing. Results The ICC of each test and the performance on the first and second attempts of individuals in the INPH group are shown in Table 3. The ICC of the first-error score was and that of the reverse-effect index was The ICCs of the indices were substantial and were comparable to those of the total FAB scores, DS backward and SCWT scores but were higher than those of the DS forward and lower than those of the PVF scores. No significant learning effect was noted for the counting-backward test or the standard neuropsychological tests with the exception of the total FAB score. The results of the counting-backward and standard neuropsychological exams for the INPH and AD groups are summarized in Table 4. Normalized data that were derived from 10 agematched, sex-matched and educationally matched healthy subjects are also shown in Table 4 for comparison purposes. The results of the firsterror score, the reverse-effect index, the total FAB, PVF, SCWT and the DS scores (forward and backward) for the INPH group were significantly worse than those observed for the AD group. In addition, the FAB subtest scores for phonemic verbal fluency, Luria motor sequence and the go/no-go test for the INPH group were significantly worse than those recorded for the AD group. Correlations between the first-error score and the reverse-effect index as well as the performance results of the standard neuropsychological tests in the INPH group are shown in Table 5. We found that the first-error score was significantly correlated with the FAB total score, the scores on the phonemic verbal fluency and the 282

5 The counting-backward test for executive function in INPH Table 3 Intraclass correlation coefficients (ICCs) and practice effects of the neuropsychological test scores in the patients with INPH Variables ICC First assessment Median (range) Second assessment P-value a Counting-backward test First-error score (0 17) 5.0 (0 to 17) Reverse-effect ( ) 10.7 ( 0.1 to 60.7) index FAB Total score (5 17) 12.0 (7 to 18) 0.006** PVF Total number of (2 23) 11.0 (2 to 26) words SCWT Error rate (%) ( ) 18.3 (0.0 to 86.7) (set 3) Digit span Forward (3 6) 5.0 (3 to 7) Backward (1 4) 3.0 (1 to 5) INPH, idiopathic normal pressure hydrocephalus; FAB, Frontal Assessment Battery; PVF, phonemic verbal fluency test; SCWT, Stroop colour-word test. * P < 0.05; ** P < a Wilcoxon signed rank test was used. go/no-go FAB subtests, the PVF score and the SCWT score. The reverse-effect index was significantly correlated with the total FAB score, in addition to scores on the similarities, phonemic verbal fluency and conflicting instructions of the FAB subtests. Moreover, the PVF score was also significantly correlated with the reverse-effect index. However, neither the first-error score nor the reverse-effect index was significantly correlated with the score on the Luria motor sequence FAB subtest or the DS score. In the AD group, the first-error score and the countingbackward effect were not significantly correlated with any of the scores on the neuropsychological tests except for the SCWT score (which was correlated with the first-error score, r s = 0.517, P = 0.02). For the logistic regression analysis, the firsterror score, the reverse-effect index, and the total FAB, PVF, SCWT and DS scores were selected to predict the diagnosis of INPH. The best predictor of an INPH diagnosis was the first-error score (odds ratio = 0.751, 95% CI = ), which was able to correctly identify 70% of the patients with INPH (14/20) and 85% of the patients with AD (17/20). The area under the ROC curve of the first-error score was (Fig. 1). The ROC curve yielded the optimal cutoff value for the first-error score (>3.25), and based on this cut-off value, the sensitivity was 80% and the specificity was 85%. Discussion This study demonstrated that the two indices of the counting-backward test are valid measures of executive dysfunction in INPH, and that the firsterror score can differentiate INPH from AD more accurately than any other standard execu- Table 4 Neuropsychological test scores (median, range) in the patients with INPH and AD Variables INPH (n = 20) AD (n = 20) NC (n = 10) P-value a Counting-backward test First-error score 5.3 (0 17) 0.8 (0 10) 1.6 (0 3.8) <0.001** Reverse-effect index 12.8 ( ) 6.4 ( ) 3.5 ( ) 0.013* FAB Total score 11.0 (5 17) 13 (9 18) 15.0 (13 17) 0.003** Subtest score Similarities 1.0 (0 3) 1.5 (0 3) 2.0 (1 3) Phonemic verbal fluency 1.0 (0 3) 2.0 (1 3) 3.0 (1 3) 0.013* Luria motor sequence 1.0 (0 3) 1.0 (1 3) 2.0 (1 3) 0.009** Conflicting instruction 3.0 (1 3) 3.0 (2 3) 3.0 (3) Go/no-go test 1.5 (0 3) 2.5 (0 3) 2.5 (1 3) 0.010* Prehension behaviour 3.0 (3) 3.0 (3) 3.0 (3) PVF Total number of words 12 (2 23) 19 (7 31) 22.0 (12 33) 0.001** SCWT Error rate (%) (set 3) 21.7 (0 63.3) 6.7 (0 33.3) 3.3 (0 10) 0.011* Digit span Forward 5.0 (3 6) 5.0 (4 6) 6.0 (4 7) 0.046* Backward 3.5 (1 4) 4.0 (2 5) 4.0 (2 5) 0.021* INPH, idiopathic normal pressure hydrocephalus; AD, Alzheimer's disease; NC, normal controls; FAB, Frontal Assessment Battery; PVF, phonemic verbal fluency test; SCWT, Stroop colour-word test. All P-values are the results of comparison between the INPH and AD patient groups. * P < 0.05; ** P < a Mann Whitney U-test was used. 283

6 Kanno et al. Table 5 Associations between counting-backward test scores and standard neuropsychological test scores in the patients with INPH Variables First-error score Reverse-effect index r s P-value r s P-value MMSE Total score * ** FAB Total score ** <0.001** Subtest score Similarities * Phonemic verbal fluency * * Luria motor sequence Conflicting instruction ** Go/no-go test * Prehension behaviour N/D N/D N/D N/D PVF Total numbers of words * ** SCWT Error rate (set 3) ** Digit span Forward Backward INPH, idiopathic normal pressure hydrocephalus; FAB, Frontal Assessment Battery; PVF, phonemic verbal fluency test; SCWT, Stroop colour-word test; N/D, not detected; MMSE, Mini-Mental State Examination. * P < 0.05; ** P < Figure 1. Receiver operating characteristic (ROC) curve of the first-error score for differentiating INPH from Alzheimer s disease. AUC, area under the ROC curve. tive function test. Although the MMSE is one of the most widely used neuropsychological tools for evaluating a subject s cognitive function, the scores of the MMSE do not entirely verify the equivalence of the severity of cognitive dysfunction between INPH and AD patients. Nonetheless, based on the subset scores of the ADAS, the severity of memory disturbance, which is a characteristic feature of cognitive dysfunction in patients with AD, was at least equivalent between INPH and AD patients in this study. Therefore, we believe that the validity of the patients with AD selected for this study ensures the usefulness of the counting-backward test for differentiating patients with INPH from those with AD in a clinical setting. The test retest reliability of the first-error score was not high, and the ICC was comparable to the FAB score. Although a much higher test retest reliability for FAB has been reported when applied to patients with AD, vascular dementia (VaD) or frontotemporal dementia (FTD) (25), the modest reliability of the first-error score in this study may be attributed to the characteristics of cognitive or behavioural dysfunction in INPH such as severe attention deficits or apathy (8, 26), rather than being a property of the test itself. However, in patients with INPH, we found that the FAB showed a learning effect, but the countingbackward test did not. Although the learning effect on neuropsychological or motor tests is unremarkable in patients with INPH (27), this feature of the counting-backward test would be more advantageous for repeated measures than the FAB. Performance on the three FAB subtests (phonemic verbal fluency, Luria motor sequence and the go/no-go test), the SCWT score and the DS scores were significantly worse for patients with INPH than for those with AD. This finding represents the deficits observed in sequential motor learning, attention and working memory, and this is consistent with the results obtained in previous studies (14, 28 30). This finding also represents the deficits of response initiation and suppression. The first-error score of patients with INPH was especially worse than that of patients with AD, and this score had strong correlations with scores obtained from the FAB go/no-go subtest and the SCWT. Therefore, as we hypothesized, the patient s failure to count backwards is associated with a deficit of the suppressed response, which leads to the inappropriate use of the routine schema (the process of counting forwards). Because the first-error score was the best predictor of INPH, it indicates that a deficit of response suppression is another main cognitive characteristic of INPH. In contrast, the reverse-effect index in patients with INPH revealed stronger correlations between the FAB conflicting-instruction subtest score and the PVF score than did the first-error score, although this index was not associated with the deficit of response suppression. This finding implies that the reverse-effect index represents the severity of executive dysfunction in additional 284

7 The counting-backward test for executive function in INPH areas, including deficits of response initiation and resistance to interference. An apparent limitation of this study was the lack of comparison among patients demonstrating subcortical or frontal dementia, including VaD, in which executive dysfunction is characterized by prominent deficits in maintaining a mental set, psychomotor speed and working memory (31). In addition, motor and urinary symptoms observed in VaD are also similar to those observed in INPH (32, 33). Further studies are needed to clarify the difference between the cognitive profiles of INPH and VaD based on an accurate diagnosis. Additionally, further studies are needed to determine the effectiveness of the counting-backward test for predicting the shunt response, and the role of this test in the CSF tap test and the external CSF drainage test. Acknowledgements We thank the patients and their families for their participation in this study. 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