Original Paper Received: November 9, 2015 Accepted: December 7, 2015 Published online: February 17, 2016
Eur Neurol 2016;75:96–103 DOI: 10.1159/000443206
Abnormal White Matter Integrity in Elderly Patients with Idiopathic Normal-Pressure Hydrocephalus: A Tract-Based Spatial Statistics Study Kyunghun Kang a–c Woohyuk Choi d Uicheul Yoon d Jong-Min Lee c Ho-Won Lee a, b
Department of Neurology, School of Medicine and b Brain Science and Engineering Institute, Kyungpook National University, Daegu, c Department of Biomedical Engineering, Hanyang University, Seoul, and d Department of Biomedical Engineering, College of Health and Medical Science, Catholic University of Daegu, Gyeongsan-si, South Korea
Key Words Diffusion tensor imaging · Normal-pressure hydrocephalus · Alzheimer’s disease
Abstract We investigated white matter integrity utilizing diffusion tensor imaging in patients with idiopathic normal-pressure hydrocephalus (INPH) who had a positive response to the cerebrospinal fluid tap test and in age- and gender-matched Alzheimer’s disease (AD) patients. We enrolled 28 patients with INPH, 28 patients with AD and 20 healthy controls. Tract-based spatial statistics demonstrated that INPH patients had lower fractional anisotropy (FA) in the anterior corona radiate (bilateral), corpus callosum, superior longitudinal fasciculus (bilateral), posterior thalamic radiation (bilateral), external capsule (bilateral) and middle cerebellar peduncle in comparison with the AD and control groups. Volume-of-interest analysis revealed that INPH patients, when compared to the AD and control groups, showed higher mean diffusivity in the anterior corona radiate (bilateral), corpus callosum, superior longitudinal fasciculus (bilateral),
© 2016 S. Karger AG, Basel 0014–3022/16/0752–0096$39.50/0 E-Mail [email protected] www.karger.com/ene
posterior thalamic radiation (left), external capsule (bilateral) and middle cerebellar peduncle. And gait dysfunction was significantly correlated with decreased FA in the splenium of the corpus callosum and right external capsule in INPH patients. Our findings may suggest a possibility for considering microstructural changes in white matter integrity in elderly patients as potential imaging markers for differentiation between INPH and AD and may help us understand the potential pathophysiology of gait disturbances associated with INPH. © 2016 S. Karger AG, Basel
Introduction
Idiopathic normal-pressure hydrocephalus (INPH) is relatively uncommon. Nevertheless, accurate diagnosis of INPH remains important because INPH is regarded as a potentially treatable syndrome by shunt surgery [1].
K.K. and W.C. contributed equally to this manuscript as first authors.
Ho-Won Lee, MD, PhD Department of Neurology, School of Medicine, Brain Science and Engineering Institute Kyungpook National University, 50 Samdeok-dong 2-ga Jung-gu, Daegu 700-721 (South Korea) E-Mail neuromd @ knu.ac.kr
Downloaded by: Univ. of California Santa Barbara 198.143.33.17 - 3/10/2016 1:27:38 PM
a
DTI in INPH and AD
tionships between DTI-based findings and clinical characteristics. In this study, we investigated white matter integrity utilizing DTI and an observer-independent tract-based spatial statistics (TBSS) analysis in 3 groups: (1) INPH patients who had a positive response to the CSFTT, (2) age- and gender-matched AD patients and (3) healthy controls. The aims of the study are (1) to evaluate differences in the topographic distribution of white matter integrity among the 3 groups, making no apriori assumptions about the location of possible abnormalities and (2) to determine whether there was any relationship between white matter integrity and various clinical profiles in INPH patients.
Materials and Methods Participants INPH participants were prospectively recruited from patients who visited the Center for Neurodegenerative Diseases of Kyungpook National University Medical Center, South Korea, from July 2011 to November 2014. The diagnosis of INPH was made using the criteria proposed by Relkin et al. [5]. A lumbar tap removing 30–50 ml of CSF was performed on all INPH patients. After the tap, all patients were re-evaluated using the INPH Grading Scale (INPHGS), the Korean-Mini Mental State Examination (KMMSE) and the Timed Up and Go Test (TUG). Changes in gait were evaluated repeatedly over 7 days after the tap, while changes in cognition and urination were evaluated at 1 week. Response to the CSFTT was defined by these 3 major scales [3]. We enrolled INPH patients who had a positive response to the CSFTT according to the Japanese guidelines for INPH [3]. AD patients and healthy controls were chosen at random from our hospital and were matched to INPH patients based on age and gender. AD was diagnosed according to NINCDS-ADRDA criteria [11]. Healthy control subjects were selected on the basis of a normal result on the K-MMSE and normal neurologic examination findings. Assessing Illness Severity The evaluation included the following scales: K-MMSE, Clinical Dementia Rating Scale (CDR), Frontal Assessment Battery, Trail Making Test Part A, INPHGS, TUG, 10-meter walking test and Gait Status Scale. Image Acquisition and Data Preprocessing MRI data were obtained using a 3.0-tesla system (GE Discovery MR750, GE Healthcare) with a 32-channel head coil. The DTI data were acquired using a single-shot echo-planar acquisition with the following parameters: 45 non-collinear diffusion gradient directions; TR = 9,900 ms; TE = 76 ms; acquisition matrix = 128 × 128; field of view = 240 mm; slice thickness = 2 mm without a gap; flip angle = 90 degrees; b-factor = 600 s/mm2; ASSET acceleration factor 2; total acquisition time 7 min 45 s. We performed DTI in INPH patients before the CSFTT.
Eur Neurol 2016;75:96–103 DOI: 10.1159/000443206
97
Downloaded by: Univ. of California Santa Barbara 198.143.33.17 - 3/10/2016 1:27:38 PM
INPH is an adult-onset syndrome of uncertain origin, showing symptoms of cognitive impairment, gait disturbance and urinary dysfunction, which involves non-obstructive enlargement of the cerebral ventricles, along with normal cerebrospinal fluid (CSF) pressure at lumbar puncture [2]. Patients with INPH may present with varying combinations or degrees of each of these classic clinical symptoms. The CSF tap test (CSFTT) has been regarded as a valuable examination for the diagnosis and prediction of shunt effectiveness in patients with INPH [3]. Clinical improvement after the CSFTT is an important metric that enhances diagnostic certainty from possible to probable, following the Japanese guideline [3]. And shunt surgery is indicated for patients with INPH who exhibit a positive CSFTT response [3]. Furthermore, the CSFTT has a high positive predictive value for successful shunt surgery [3]. Therefore, the CSFTT is generally recommended as a key step in the diagnosis of INPH [3]. Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Gait disturbance is well known to be common in AD [4]. Patients with AD have diffuse cerebral atrophy, leading to secondary ventricular enlargement. Furthermore, cerebral atrophy as a result of aging can also exacerbate ventricular dilatation. Non-obstructive enlargement of the cerebral ventricles in INPH can be difficult to distinguish from AD- and age-related ex vacuo ventricular enlargement by routine MRI. Therefore, in elderly patients, AD may present similarly in patients with INPH [5]. It is often difficult to distinguish INPH from AD by the clinical and routine MRI findings alone; therefore, further additional tests are needed. Disorders of white matter are generally considered as the principal pathological hallmarks of INPH. It has been suggested that characteristic white matter changes can precipitate the characteristic symptoms of INPH [2]. In AD, along with a well-known cortical pathology, white matter microstructural alterations also have been demonstrated [6]. Diffusion tensor imaging (DTI) is a useful magnetic resonance technique enabling the noninvasive and detailed analysis of subcortical white matter structures in the human brain and is sensitive to microstructural changes in white matter integrity that are not always detectable by routine MRI [7]. To date, there have been several DTI investigations of these patients [6, 8–10], but their results are limited by an a priori region of interest approach, a small number of participants and clinical evaluation parameters, and a lack of analysis of the rela-
Table 1. Demographic data, clinical characteristics, CSF drainage volume, CSF opening pressure and Evan’s ratio
Characteristics
INPH (n = 28)
Gender, male Age, years Education, yearsa Duration of symptoms, years K-MMSEb CDR (0:0.5:1:2:3) INPHGS GS-gait GS-cogn GS-urin Total TUG 10-meter walking test GSS FAB TMT-A Drainage volume of CSF CSF opening pressure (cm H2O) Evan’s ratio
19 (67.9) 74.0±3.5 10.1±4.3 1.8±0.9 19.2±7.6 0:14:9:2:3
AD (n = 28)
Control (n = 20)
Post-hoc test, p value
13 (46.4) 73.9±5.5 7.4±3.7 2.4±2.0 19.1±4.8 0:8:17:3:0
8 (40.0) 71.8±3.9 10.3±4.7
0.016c
0.057
0.891
27.5±2.1
0.321
Eur Neurol 2016;75:96–103 DOI: 10.1159/000443206
Abnormal White Matter Integrity in Elderly Patients with Idiopathic Normal-Pressure Hydrocephalus: A Tract-Based Spatial Statistics Study Kyunghun Kang a–c Woohyuk Choi d Uicheul Yoon d Jong-Min Lee c Ho-Won Lee a, b
Department of Neurology, School of Medicine and b Brain Science and Engineering Institute, Kyungpook National University, Daegu, c Department of Biomedical Engineering, Hanyang University, Seoul, and d Department of Biomedical Engineering, College of Health and Medical Science, Catholic University of Daegu, Gyeongsan-si, South Korea
Key Words Diffusion tensor imaging · Normal-pressure hydrocephalus · Alzheimer’s disease
Abstract We investigated white matter integrity utilizing diffusion tensor imaging in patients with idiopathic normal-pressure hydrocephalus (INPH) who had a positive response to the cerebrospinal fluid tap test and in age- and gender-matched Alzheimer’s disease (AD) patients. We enrolled 28 patients with INPH, 28 patients with AD and 20 healthy controls. Tract-based spatial statistics demonstrated that INPH patients had lower fractional anisotropy (FA) in the anterior corona radiate (bilateral), corpus callosum, superior longitudinal fasciculus (bilateral), posterior thalamic radiation (bilateral), external capsule (bilateral) and middle cerebellar peduncle in comparison with the AD and control groups. Volume-of-interest analysis revealed that INPH patients, when compared to the AD and control groups, showed higher mean diffusivity in the anterior corona radiate (bilateral), corpus callosum, superior longitudinal fasciculus (bilateral),
© 2016 S. Karger AG, Basel 0014–3022/16/0752–0096$39.50/0 E-Mail [email protected] www.karger.com/ene
posterior thalamic radiation (left), external capsule (bilateral) and middle cerebellar peduncle. And gait dysfunction was significantly correlated with decreased FA in the splenium of the corpus callosum and right external capsule in INPH patients. Our findings may suggest a possibility for considering microstructural changes in white matter integrity in elderly patients as potential imaging markers for differentiation between INPH and AD and may help us understand the potential pathophysiology of gait disturbances associated with INPH. © 2016 S. Karger AG, Basel
Introduction
Idiopathic normal-pressure hydrocephalus (INPH) is relatively uncommon. Nevertheless, accurate diagnosis of INPH remains important because INPH is regarded as a potentially treatable syndrome by shunt surgery [1].
K.K. and W.C. contributed equally to this manuscript as first authors.
Ho-Won Lee, MD, PhD Department of Neurology, School of Medicine, Brain Science and Engineering Institute Kyungpook National University, 50 Samdeok-dong 2-ga Jung-gu, Daegu 700-721 (South Korea) E-Mail neuromd @ knu.ac.kr
Downloaded by: Univ. of California Santa Barbara 198.143.33.17 - 3/10/2016 1:27:38 PM
a
DTI in INPH and AD
tionships between DTI-based findings and clinical characteristics. In this study, we investigated white matter integrity utilizing DTI and an observer-independent tract-based spatial statistics (TBSS) analysis in 3 groups: (1) INPH patients who had a positive response to the CSFTT, (2) age- and gender-matched AD patients and (3) healthy controls. The aims of the study are (1) to evaluate differences in the topographic distribution of white matter integrity among the 3 groups, making no apriori assumptions about the location of possible abnormalities and (2) to determine whether there was any relationship between white matter integrity and various clinical profiles in INPH patients.
Materials and Methods Participants INPH participants were prospectively recruited from patients who visited the Center for Neurodegenerative Diseases of Kyungpook National University Medical Center, South Korea, from July 2011 to November 2014. The diagnosis of INPH was made using the criteria proposed by Relkin et al. [5]. A lumbar tap removing 30–50 ml of CSF was performed on all INPH patients. After the tap, all patients were re-evaluated using the INPH Grading Scale (INPHGS), the Korean-Mini Mental State Examination (KMMSE) and the Timed Up and Go Test (TUG). Changes in gait were evaluated repeatedly over 7 days after the tap, while changes in cognition and urination were evaluated at 1 week. Response to the CSFTT was defined by these 3 major scales [3]. We enrolled INPH patients who had a positive response to the CSFTT according to the Japanese guidelines for INPH [3]. AD patients and healthy controls were chosen at random from our hospital and were matched to INPH patients based on age and gender. AD was diagnosed according to NINCDS-ADRDA criteria [11]. Healthy control subjects were selected on the basis of a normal result on the K-MMSE and normal neurologic examination findings. Assessing Illness Severity The evaluation included the following scales: K-MMSE, Clinical Dementia Rating Scale (CDR), Frontal Assessment Battery, Trail Making Test Part A, INPHGS, TUG, 10-meter walking test and Gait Status Scale. Image Acquisition and Data Preprocessing MRI data were obtained using a 3.0-tesla system (GE Discovery MR750, GE Healthcare) with a 32-channel head coil. The DTI data were acquired using a single-shot echo-planar acquisition with the following parameters: 45 non-collinear diffusion gradient directions; TR = 9,900 ms; TE = 76 ms; acquisition matrix = 128 × 128; field of view = 240 mm; slice thickness = 2 mm without a gap; flip angle = 90 degrees; b-factor = 600 s/mm2; ASSET acceleration factor 2; total acquisition time 7 min 45 s. We performed DTI in INPH patients before the CSFTT.
Eur Neurol 2016;75:96–103 DOI: 10.1159/000443206
97
Downloaded by: Univ. of California Santa Barbara 198.143.33.17 - 3/10/2016 1:27:38 PM
INPH is an adult-onset syndrome of uncertain origin, showing symptoms of cognitive impairment, gait disturbance and urinary dysfunction, which involves non-obstructive enlargement of the cerebral ventricles, along with normal cerebrospinal fluid (CSF) pressure at lumbar puncture [2]. Patients with INPH may present with varying combinations or degrees of each of these classic clinical symptoms. The CSF tap test (CSFTT) has been regarded as a valuable examination for the diagnosis and prediction of shunt effectiveness in patients with INPH [3]. Clinical improvement after the CSFTT is an important metric that enhances diagnostic certainty from possible to probable, following the Japanese guideline [3]. And shunt surgery is indicated for patients with INPH who exhibit a positive CSFTT response [3]. Furthermore, the CSFTT has a high positive predictive value for successful shunt surgery [3]. Therefore, the CSFTT is generally recommended as a key step in the diagnosis of INPH [3]. Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Gait disturbance is well known to be common in AD [4]. Patients with AD have diffuse cerebral atrophy, leading to secondary ventricular enlargement. Furthermore, cerebral atrophy as a result of aging can also exacerbate ventricular dilatation. Non-obstructive enlargement of the cerebral ventricles in INPH can be difficult to distinguish from AD- and age-related ex vacuo ventricular enlargement by routine MRI. Therefore, in elderly patients, AD may present similarly in patients with INPH [5]. It is often difficult to distinguish INPH from AD by the clinical and routine MRI findings alone; therefore, further additional tests are needed. Disorders of white matter are generally considered as the principal pathological hallmarks of INPH. It has been suggested that characteristic white matter changes can precipitate the characteristic symptoms of INPH [2]. In AD, along with a well-known cortical pathology, white matter microstructural alterations also have been demonstrated [6]. Diffusion tensor imaging (DTI) is a useful magnetic resonance technique enabling the noninvasive and detailed analysis of subcortical white matter structures in the human brain and is sensitive to microstructural changes in white matter integrity that are not always detectable by routine MRI [7]. To date, there have been several DTI investigations of these patients [6, 8–10], but their results are limited by an a priori region of interest approach, a small number of participants and clinical evaluation parameters, and a lack of analysis of the rela-
Table 1. Demographic data, clinical characteristics, CSF drainage volume, CSF opening pressure and Evan’s ratio
Characteristics
INPH (n = 28)
Gender, male Age, years Education, yearsa Duration of symptoms, years K-MMSEb CDR (0:0.5:1:2:3) INPHGS GS-gait GS-cogn GS-urin Total TUG 10-meter walking test GSS FAB TMT-A Drainage volume of CSF CSF opening pressure (cm H2O) Evan’s ratio
19 (67.9) 74.0±3.5 10.1±4.3 1.8±0.9 19.2±7.6 0:14:9:2:3
AD (n = 28)
Control (n = 20)
Post-hoc test, p value
13 (46.4) 73.9±5.5 7.4±3.7 2.4±2.0 19.1±4.8 0:8:17:3:0
8 (40.0) 71.8±3.9 10.3±4.7
0.016c
0.057
0.891
27.5±2.1
0.321
