Original Paper Received: May 13, 2013 Accepted: September 29, 2013 Published online: January 25, 2014
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
Cognitive Profile of CADASIL Patients with R544C Notch3 Mutation Jung-Kook Song a Young Ook Noh c Jung Seok Lee b a c
Preventive Medicine and b Department of Neurology, Jeju National University College of Medicine, Clinical Research Center, Jeju National University Hospital, Jeju, South Korea
Key Words CADASIL · R544C mutation · Dementia
Abstract Background: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. In the present study, we aimed to analyze cognitive and neuroimaging profiles of CADASIL patients with R544C mutation. Methods: Fifty-eight consecutive patients with R544C mutation and 26 normal controls were investigated. The patients were divided into two groups depending on the presence (CADASIL with dementia: CADASIL-D) or absence of dementia (CADASIL no dementia: CADASIL-ND). We applied the same neuropsychological test to the three groups. Brain magnetic resonance images were obtained from 58 patients with R544C mutation. Linear regression models were used to assess the impact of lacunes and white matter hyperintensities on cognitive function in the CADASIL-ND group. Results: Compared to controls, the CADASIL-ND group demonstrated significant difficulties concerning measures of attention, executive function, and motor control. The CADASIL-D group was impaired in all cognitive domains that were assessed, except the language domain. After correction for age and educational level, the number of lacunes was associated with lower scores in the Alzheimer’s Disease Assessment Scale cognitive subtest and Stroop color test in the CADASIL-ND group. Conclusions:
© 2014 S. Karger AG, Basel 0014–3022/14/0716–0217$39.50/0 E-Mail [email protected] www.karger.com/ene
Non-Caucasian CADASIL patients with R544C mutation and Caucasian CADASIL patients show similar patterns of cognitive impairment. © 2014 S. Karger AG, Basel
Introduction
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited angiopathy caused by mutations in the Notch3 gene [1]. The main clinical manifestations are recurrent stroke, cognitive decline, chronic headache, mood disturbances, and seizure [2, 3]. Cognitive impairment is the second most frequent clinical manifestation. Recent studies have shown that patients demonstrate frontal lobe dysfunction and slowness of cognitive processing speed in the early stage, namely the pre-dementia stage of CADASIL [4–6]. There seem to be some differences between Caucasian and East Asian patients with CADASIL in clinical phenotypes and neuroimaging features. East Asian patients have higher rates of intracranial hemorrhage (ICH) than Caucasian patients [7, 8]. Also, hyperintensities of the anterior temporal pole, considered a characteristic magnetic resonance imaging (MRI) feature in CADASIL, are found less often in East Asian patients [8–10]. The majority of East Asian patients with CADASIL carry the same R544C mutation [7–9]. However, R544C mutation has rarely been Jung Seok Lee, MD Department of Neurology, Jeju National University Hospital 1 Ara 1-dong, Jeju-si, Jeju-do 690-756 (South Korea) E-Mail nrlee71 @ naver.com
reported as a site of mutations in Caucasian patients [11]. Although the profile of cognitive deficits in CADASIL has been described previously for Caucasians [4–6], that of Asian patients has not been thoroughly evaluated. Therefore, we sought to elucidate the cognitive profile of CADASIL patients with R544C mutation, and to analyze if MRI markers (number of lacunes and white matter hyperintensities, WMHs) had an independent effect on cognition in CADASIL patients without dementia. Methods Subjects Between April 2008 and December 2009, we administered a detailed neuropsychological test and brain MRI to 58 consecutive patients with R544C mutation from 46 Korean families who had genetically confirmed CADASIL at Jeju National University Hospital. Patients were divided into two groups, depending on the presence (CADASIL-D group) and absence of dementia (CADASIL-ND group). The CADASIL-D group (n = 6) fulfilled the DSM-IV criteria for dementia and all of them had experienced one or more strokes. The control group consisted of 26 healthy subjects. The vascular risk factors were recorded, including hypertension, diabetes mellitus, and hypercholesterolemia. Hypertension was defined as blood pressure >140/90 mm Hg on different occasions or use of an antihypertensive agent. Diabetes mellitus was defined as a fasting glucose level of ≥126 mg/dl, a PP2 test level of ≥200 mg/dl, or the use of antidiabetes medication. Hypercholesterolemia was defined as a total serum cholesterol level of >240 mg/dl. This study was approved by the institutional review board at our institution, and informed consent was obtained from all participants. Neuropsychological Assessment All participants underwent detailed neuropsychological testing adapted for use with native Korean speakers. The cognitive examination includes the following tests: The Mini-Mental State Examination (MMSE) [12], Alzheimer’s Disease Assessment Scale cognitive subtest (ADAS-cog) [13], Vascular Dementia Assessment Scale cognitive subscale extension (VADAS-cog extension) [14], Stroop test [15] and Trail Making Test part A (TMT-A) and part B (TMT-B) [16]. The VADAS-cog extension includes six additional subtests (delayed word recall task, symbol digit modalities test, digit backward test, maze task, digit cancellation task, and verbal fluency test). Global cognitive function was assessed with the MMSE and ADAS-cog. Tests were grouped by cognitive domain. There were three measures of executive function (Stroop, verbal fluency test, and TMT-B), two measures of attention (digit cancellation task and symbol digit modalities test), two measures of speed and motor control (TMT-A and time to complete maze test), four measures of memory (word recall, word recognition, remembering test instructions, delayed word recall task), two measures of language (command and naming), and two measures of praxis (constructional and ideational praxis). In addition to these neuropsychological tests, activities of daily living attributable to cognitive deficits were assessed based on the Seoul-Instrumental Activities of Daily Living (S-IADL) [17]. The S-IADL score was determined
218
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
using a 15-item questionnaire regarding the activities. The S-IADL scores ranged from 0 to 45, a higher score indicating lower performance. The neuropsychological examinations were performed by a trained neuropsychologist who was blinded to the patient imaging results. MRI Procedure All patients with R544C mutation had an MRI scan on a 1.5-tesla system (Sonata; Siemens, Erlangen, Germany). The brain imaging protocol included the following (all protocols used a slice thickness of 5 mm and an inter-slice gap of 1.5 mm): T1-weighted images (time to echo, TE = 9.3 ms and time to repeat, TR = 550 ms), T2*-weighted gradient echo planar images (TE = 20 ms and TR = 600 ms), and FLAIR (fluid-attenuated inversion recovery) images (TE = 135 ms and TR = 8,100 ms). Lacunar infarcts were defined as parenchymal defect not extending to the cortical gray matter with a signal intensity of CSF in all sequences and more than 2 mm in diameter. The lesions located in the lower third of the corpus striatum of the basal ganglia were excluded [18]. WMHs were defined as white matter areas of increased signal intensity on FLAIR images. All FLAIR axial sections from the base of the cerebellum to the vertex were analyzed. A masking and thresholding technique was used (Analyze 8.1, Biomedical Imaging, Mayo Clinic, Rochester, USA). The software then automatically calculated the total volume of WMH by multiplying lesion area by section thickness. WMH volume was corrected for total brain volume by dividing the individual WMH volume by the intracranial cavity volume (normalized WMH volume; nWMHs). WMH volume measurements were performed by 2 investigators blinded to clinical information. Statistical Analysis Statistical analyses were performed with SPSS-18 for Windows. The differences in demographics and S-IADL among three groups (controls, CADASIL-ND group, and CADASIL-D group) were assessed with ANOVA with subsequent Scheffe post hoc test or χ2 tests. We conducted an ANCOVA to compare the neuropsychological scores among the three groups, adjusting for age and educational level. We also used a univariate and multivariate regression model to test the association of MRI markers with the cognitive function in the CADASIL-ND group. The multivariate model was adjusted for age and educational level. Probability values less than 0.05 were accepted as statistically significant.
Results
The demographic data of all participants’ characteristics are reported in table 1. Ischemic stroke was the most frequent manifestation (n = 25), followed by chronic headache (n = 18), transient ischemic attack (n = 7), dementia (n = 6), Parkinsonism (n = 4), ICH (n = 4; fig. 1) and seizure (n = 2). The results of cognitive function tests are presented in table 2. The CADASIL-ND group performed poorer than the controls in eight tests: delayed word recall (p < 0.01), verbal fluency (p < 0.01), correct responses of symbol digSong/Noh/Lee
a
b
c
d
e
f
Fig. 1. FLAIR image (a, b), T1-weighted image (c, d), and T2*-weighted gradient echo image (e, f) from the patient with
CADASIL showing periventricular and deep white matter hyperintensities (a, b), multiple lacunes (c, d), and ICH (e, f).
Table 1. General characteristics of the CADASIL-ND group, CADASIL-D group, and controls
Age, years Male/female Education, years S-IADL score
Control (n = 26)
CADASIL-ND (n = 52)
CADASIL-D (n = 6)
χ2 or F
ANOVA p
Post hoc
57.8 (11.5) 8/18 10.9 (3.6) 1.9 (2.1)
59.4 (12.0) 28/24 9.0 (5.4) 2.4 (3.2)
72.3 (10.7) 2/4 4.2 (6.1) 20.0 (14.3)
3.80 4.09 4.65 40.98
0.026 0.129 0.038 0.000
a, b < c a, b > c a, b > c
Figures in parentheses indicate standard deviation. a = Control; b = CADASIL-ND; c = CADASIL-D.
it modalities (p < 0.01), time of maze test (p < 0.05), time of TMT-A (p < 0.001), time of TMT-B (p < 0.001), correct responses of the Stroop word test (p < 0.001), and correct responses of the Stroop color test (p < 0.001). There were no significant differences between the control and CADASIL-ND groups in the MMSE and ADAS-cog. The CADASIL-D group was significantly more impaired than the CADASIL-ND group and control group on all but one measure of language (command) and one measure of praxis (ideational praxis). Five of six CADASIL-D patients could not perform TMT-B. Of the 52 CADASIL-ND patients, 28 (53.8%) had lacunar infarcts, with 5.9 ± 6.7 (range 1–30) per patient. The nWMHs was 2.3 ± 1.7. There were no significant differences in cardiovascular risk factors (hypertension, dia-
betes mellitus, and hypercholesterolemia) between the control and CADASIL-ND groups (table 3). Results of linear regression analyses to evaluate the impact of MRI markers (number of lacunes and nWMHs) on scores for different neuropsychological tests (MMSE, ADAScog, verbal fluency test and Stroop color test) in the CADASIL-ND group are shown in table 4. The number of lacunes influenced the performance on the global measure of cognition (ADAS-cog total score) and the measure of executive function (Stroop color test). nWMHs were related to lower performance on the ADAS-cog (p < 0.001, β = 0.503), and the Stroop color test (p = 0.004, β = –0.409), but these associations disappeared in the final multivariate model. Education interfered with all neuropsychological tests.
CADASIL Patients with R544C Notch3 Mutation
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
219
Table 2. Comparison of cognitive function in the CADASIL groups and controls
Control
CADASIL-ND
CADASIL-D
ANCOVA F
MMSE ADAS-cog, memory Word recall Word registration Remembering test instruction Subsets Command Constructional apraxia Naming Ideational praxis Orientation Spoken language ability Word finding difficulty Comprehension Concentration ADAS-cog total Delayed word recall Verbal fluency Digit span backward Symbol digit modalities, correct Symbol digit modalities, errors Digit cancellaion test, correct Digit cancellaion test, errors Maze task, time Maze task, errors TMT-A, time TMT-A, errors TMT-B, time TMT-B, errors Stroop, word reading, correct Stroop, word reading, errors Stroop, color reading, correct Stroop, color reading, errors
Post hoc p
28.9 (1.0)
27.8 (2.5)
15.4 (8.7)
47.16
c
4.3 (1.5) 2.0 (1.5) 0.1 (0.3)
4.7 (1.7) 3.2 (3.1) 0.3 (0.7)
7.5 (1.3) 7.0 (3.9) 2.0 (2.2)
4.54 4.49 9.81
c
0.3 (1.1) 0.5 (0.9) 0.0 (0.0) 0.5 (0.5) 0.4 (0.2) 0.0 (0.0) 0.0 (0.2) 0.2 (0.4) 0.1 (0.3) 8.3 (3.4) 3.1 (1.8) 18.6 (5.3) 6.3 (2.4) 38.7 (14.3) 1.6 (2.5) 25.1 (7.2) 0.1 (0.3) 6.8 (3.6) 0.1 (0.3) 21.7 (9.7) 0.0 (0.2) 43.2 (21.0) 0.5 (0.7) 111.5 (1.6) 0.2 (0.4) 95.5 (19.9) 2.7 (3.8)
0.1 (0.4) 0.5 (0.6) 0.0 (0.0) 0.6 (0.6) 0.2 (0.4) 0.2 (0.4) 0.3 (0.5) 0.5 (0.8) 0.3 (0.7) 10.9 (6.4) 4.0 (2.2) 14.6 (5.2) 5.1 (1.7) 29.6 (18.6) 1.4 (1.8) 22.1 (9.4) 0.1 (0.3) 10.8 (7.5) 0.2 (0.5) 64.0 (37.3) 0.3 (0.6) 142.2 (87.5) 1.4 (1.8) 104.3 (13.8) 0.9 (2.0) 78.3 (27.7) 2.9 (4.8)
0.3 (0.5) 2.0 (1.4) 0.0 (0.0) 1.0 (0.8) 4.3 (2.1) 1.8 (1.7) 1.8 (1.5) 2.0 (2.2) 0.5 (1.0) 27.8 (5.7) 7.3 (1.2) 7.3 (2.3) 3.7 (1.5) 10.0 (5.6) 1.3 (1.5) 8.7 (3.1) 0.3 (0.6) 15.0 (13.7) 11.0 (18.2) 147.5 (88.3) 0.5 (0.7) 150.0 1.8 28.5 (22.0) 1.5 (0.7) 27.5 (13.4) 5.5 (4.9)
1.12 6.68
0.332 c
0.33 104.43 20.71 19.10 7.43 0.58 20.46 6.26 8.38 3.09 6.01 0.07 6.03 0.72 3.17 19.16 34.04 1.76 21.78 2.56 69.91 1.77 11.45 0.21
0.718 b>c a > b, c a>b>c a>b>c
Scores in parentheses represent standard deviation. Analysis of cognitive function was performed using ANCOVA with age and education adjustment. a = Control; b = CADASIL-ND; c = CADASIL-D. * p < 0.05; ** p < 0.01; *** p < 0.001.
Discussion
We found that executive dysfunction and slow processing speed were apparent even in patients without dementia (CADASIL-ND group), suggesting that CADASIL manifests as frontal lobe dysfunction in the early stage. To our knowledge, this is the first study on cognitive decline of CADASIL in a non-Caucasian population. The earliest sign of CADASIL is impairment in the executive function and processing speed. The study of Pe220
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
ters et al. [5] compared the cognitive function of patients with CADASIL and controls, and then compared the cognitive function between patients with no or mild impairment and those with advanced deficit. Patients with no or mild impairment performed poorer than controls in executive function, attention, and motor control. In our study, the CADASIL-ND group showed considerable decline in the executive function, attention, memory and motor control compared to matched controls. Thus, this pattern of cognitive deficit is consistent with the findings Song/Noh/Lee
Table 3. Distribution of major cardiovascular risk factors
Variable
Controls (n = 26)
CADASIL-ND (n = 52)
p
Hypertension Diabetes Hypercholesterolemia
10 (38.5) 2 (7.7) 3 (11.5)
23 (44.2) 6 (11.5) 10 (19.2)
0.627 0.712 0.526
Figures in parentheses indicate percentages.
Table 4. Influence of MRI markers on neuropsychological evalua-
tion in the CADASIL-ND group Cognitive measures
Independent variables
β standard
p value
MMSE
Age Education Lacunes nWMHs Age Education Lacunes nWMHs Age Education Lacunes nWMHs Age Education Lacunes nWMHs
–0.026 0.633 –0.13 0.047 0.055 –0.475 0.382 0.203 –0.201 0.445 –0.136 0.18 0.026 0.604 –0.237 –0.181
0.905
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
Cognitive Profile of CADASIL Patients with R544C Notch3 Mutation Jung-Kook Song a Young Ook Noh c Jung Seok Lee b a c
Preventive Medicine and b Department of Neurology, Jeju National University College of Medicine, Clinical Research Center, Jeju National University Hospital, Jeju, South Korea
Key Words CADASIL · R544C mutation · Dementia
Abstract Background: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. In the present study, we aimed to analyze cognitive and neuroimaging profiles of CADASIL patients with R544C mutation. Methods: Fifty-eight consecutive patients with R544C mutation and 26 normal controls were investigated. The patients were divided into two groups depending on the presence (CADASIL with dementia: CADASIL-D) or absence of dementia (CADASIL no dementia: CADASIL-ND). We applied the same neuropsychological test to the three groups. Brain magnetic resonance images were obtained from 58 patients with R544C mutation. Linear regression models were used to assess the impact of lacunes and white matter hyperintensities on cognitive function in the CADASIL-ND group. Results: Compared to controls, the CADASIL-ND group demonstrated significant difficulties concerning measures of attention, executive function, and motor control. The CADASIL-D group was impaired in all cognitive domains that were assessed, except the language domain. After correction for age and educational level, the number of lacunes was associated with lower scores in the Alzheimer’s Disease Assessment Scale cognitive subtest and Stroop color test in the CADASIL-ND group. Conclusions:
© 2014 S. Karger AG, Basel 0014–3022/14/0716–0217$39.50/0 E-Mail [email protected] www.karger.com/ene
Non-Caucasian CADASIL patients with R544C mutation and Caucasian CADASIL patients show similar patterns of cognitive impairment. © 2014 S. Karger AG, Basel
Introduction
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited angiopathy caused by mutations in the Notch3 gene [1]. The main clinical manifestations are recurrent stroke, cognitive decline, chronic headache, mood disturbances, and seizure [2, 3]. Cognitive impairment is the second most frequent clinical manifestation. Recent studies have shown that patients demonstrate frontal lobe dysfunction and slowness of cognitive processing speed in the early stage, namely the pre-dementia stage of CADASIL [4–6]. There seem to be some differences between Caucasian and East Asian patients with CADASIL in clinical phenotypes and neuroimaging features. East Asian patients have higher rates of intracranial hemorrhage (ICH) than Caucasian patients [7, 8]. Also, hyperintensities of the anterior temporal pole, considered a characteristic magnetic resonance imaging (MRI) feature in CADASIL, are found less often in East Asian patients [8–10]. The majority of East Asian patients with CADASIL carry the same R544C mutation [7–9]. However, R544C mutation has rarely been Jung Seok Lee, MD Department of Neurology, Jeju National University Hospital 1 Ara 1-dong, Jeju-si, Jeju-do 690-756 (South Korea) E-Mail nrlee71 @ naver.com
reported as a site of mutations in Caucasian patients [11]. Although the profile of cognitive deficits in CADASIL has been described previously for Caucasians [4–6], that of Asian patients has not been thoroughly evaluated. Therefore, we sought to elucidate the cognitive profile of CADASIL patients with R544C mutation, and to analyze if MRI markers (number of lacunes and white matter hyperintensities, WMHs) had an independent effect on cognition in CADASIL patients without dementia. Methods Subjects Between April 2008 and December 2009, we administered a detailed neuropsychological test and brain MRI to 58 consecutive patients with R544C mutation from 46 Korean families who had genetically confirmed CADASIL at Jeju National University Hospital. Patients were divided into two groups, depending on the presence (CADASIL-D group) and absence of dementia (CADASIL-ND group). The CADASIL-D group (n = 6) fulfilled the DSM-IV criteria for dementia and all of them had experienced one or more strokes. The control group consisted of 26 healthy subjects. The vascular risk factors were recorded, including hypertension, diabetes mellitus, and hypercholesterolemia. Hypertension was defined as blood pressure >140/90 mm Hg on different occasions or use of an antihypertensive agent. Diabetes mellitus was defined as a fasting glucose level of ≥126 mg/dl, a PP2 test level of ≥200 mg/dl, or the use of antidiabetes medication. Hypercholesterolemia was defined as a total serum cholesterol level of >240 mg/dl. This study was approved by the institutional review board at our institution, and informed consent was obtained from all participants. Neuropsychological Assessment All participants underwent detailed neuropsychological testing adapted for use with native Korean speakers. The cognitive examination includes the following tests: The Mini-Mental State Examination (MMSE) [12], Alzheimer’s Disease Assessment Scale cognitive subtest (ADAS-cog) [13], Vascular Dementia Assessment Scale cognitive subscale extension (VADAS-cog extension) [14], Stroop test [15] and Trail Making Test part A (TMT-A) and part B (TMT-B) [16]. The VADAS-cog extension includes six additional subtests (delayed word recall task, symbol digit modalities test, digit backward test, maze task, digit cancellation task, and verbal fluency test). Global cognitive function was assessed with the MMSE and ADAS-cog. Tests were grouped by cognitive domain. There were three measures of executive function (Stroop, verbal fluency test, and TMT-B), two measures of attention (digit cancellation task and symbol digit modalities test), two measures of speed and motor control (TMT-A and time to complete maze test), four measures of memory (word recall, word recognition, remembering test instructions, delayed word recall task), two measures of language (command and naming), and two measures of praxis (constructional and ideational praxis). In addition to these neuropsychological tests, activities of daily living attributable to cognitive deficits were assessed based on the Seoul-Instrumental Activities of Daily Living (S-IADL) [17]. The S-IADL score was determined
218
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
using a 15-item questionnaire regarding the activities. The S-IADL scores ranged from 0 to 45, a higher score indicating lower performance. The neuropsychological examinations were performed by a trained neuropsychologist who was blinded to the patient imaging results. MRI Procedure All patients with R544C mutation had an MRI scan on a 1.5-tesla system (Sonata; Siemens, Erlangen, Germany). The brain imaging protocol included the following (all protocols used a slice thickness of 5 mm and an inter-slice gap of 1.5 mm): T1-weighted images (time to echo, TE = 9.3 ms and time to repeat, TR = 550 ms), T2*-weighted gradient echo planar images (TE = 20 ms and TR = 600 ms), and FLAIR (fluid-attenuated inversion recovery) images (TE = 135 ms and TR = 8,100 ms). Lacunar infarcts were defined as parenchymal defect not extending to the cortical gray matter with a signal intensity of CSF in all sequences and more than 2 mm in diameter. The lesions located in the lower third of the corpus striatum of the basal ganglia were excluded [18]. WMHs were defined as white matter areas of increased signal intensity on FLAIR images. All FLAIR axial sections from the base of the cerebellum to the vertex were analyzed. A masking and thresholding technique was used (Analyze 8.1, Biomedical Imaging, Mayo Clinic, Rochester, USA). The software then automatically calculated the total volume of WMH by multiplying lesion area by section thickness. WMH volume was corrected for total brain volume by dividing the individual WMH volume by the intracranial cavity volume (normalized WMH volume; nWMHs). WMH volume measurements were performed by 2 investigators blinded to clinical information. Statistical Analysis Statistical analyses were performed with SPSS-18 for Windows. The differences in demographics and S-IADL among three groups (controls, CADASIL-ND group, and CADASIL-D group) were assessed with ANOVA with subsequent Scheffe post hoc test or χ2 tests. We conducted an ANCOVA to compare the neuropsychological scores among the three groups, adjusting for age and educational level. We also used a univariate and multivariate regression model to test the association of MRI markers with the cognitive function in the CADASIL-ND group. The multivariate model was adjusted for age and educational level. Probability values less than 0.05 were accepted as statistically significant.
Results
The demographic data of all participants’ characteristics are reported in table 1. Ischemic stroke was the most frequent manifestation (n = 25), followed by chronic headache (n = 18), transient ischemic attack (n = 7), dementia (n = 6), Parkinsonism (n = 4), ICH (n = 4; fig. 1) and seizure (n = 2). The results of cognitive function tests are presented in table 2. The CADASIL-ND group performed poorer than the controls in eight tests: delayed word recall (p < 0.01), verbal fluency (p < 0.01), correct responses of symbol digSong/Noh/Lee
a
b
c
d
e
f
Fig. 1. FLAIR image (a, b), T1-weighted image (c, d), and T2*-weighted gradient echo image (e, f) from the patient with
CADASIL showing periventricular and deep white matter hyperintensities (a, b), multiple lacunes (c, d), and ICH (e, f).
Table 1. General characteristics of the CADASIL-ND group, CADASIL-D group, and controls
Age, years Male/female Education, years S-IADL score
Control (n = 26)
CADASIL-ND (n = 52)
CADASIL-D (n = 6)
χ2 or F
ANOVA p
Post hoc
57.8 (11.5) 8/18 10.9 (3.6) 1.9 (2.1)
59.4 (12.0) 28/24 9.0 (5.4) 2.4 (3.2)
72.3 (10.7) 2/4 4.2 (6.1) 20.0 (14.3)
3.80 4.09 4.65 40.98
0.026 0.129 0.038 0.000
a, b < c a, b > c a, b > c
Figures in parentheses indicate standard deviation. a = Control; b = CADASIL-ND; c = CADASIL-D.
it modalities (p < 0.01), time of maze test (p < 0.05), time of TMT-A (p < 0.001), time of TMT-B (p < 0.001), correct responses of the Stroop word test (p < 0.001), and correct responses of the Stroop color test (p < 0.001). There were no significant differences between the control and CADASIL-ND groups in the MMSE and ADAS-cog. The CADASIL-D group was significantly more impaired than the CADASIL-ND group and control group on all but one measure of language (command) and one measure of praxis (ideational praxis). Five of six CADASIL-D patients could not perform TMT-B. Of the 52 CADASIL-ND patients, 28 (53.8%) had lacunar infarcts, with 5.9 ± 6.7 (range 1–30) per patient. The nWMHs was 2.3 ± 1.7. There were no significant differences in cardiovascular risk factors (hypertension, dia-
betes mellitus, and hypercholesterolemia) between the control and CADASIL-ND groups (table 3). Results of linear regression analyses to evaluate the impact of MRI markers (number of lacunes and nWMHs) on scores for different neuropsychological tests (MMSE, ADAScog, verbal fluency test and Stroop color test) in the CADASIL-ND group are shown in table 4. The number of lacunes influenced the performance on the global measure of cognition (ADAS-cog total score) and the measure of executive function (Stroop color test). nWMHs were related to lower performance on the ADAS-cog (p < 0.001, β = 0.503), and the Stroop color test (p = 0.004, β = –0.409), but these associations disappeared in the final multivariate model. Education interfered with all neuropsychological tests.
CADASIL Patients with R544C Notch3 Mutation
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
219
Table 2. Comparison of cognitive function in the CADASIL groups and controls
Control
CADASIL-ND
CADASIL-D
ANCOVA F
MMSE ADAS-cog, memory Word recall Word registration Remembering test instruction Subsets Command Constructional apraxia Naming Ideational praxis Orientation Spoken language ability Word finding difficulty Comprehension Concentration ADAS-cog total Delayed word recall Verbal fluency Digit span backward Symbol digit modalities, correct Symbol digit modalities, errors Digit cancellaion test, correct Digit cancellaion test, errors Maze task, time Maze task, errors TMT-A, time TMT-A, errors TMT-B, time TMT-B, errors Stroop, word reading, correct Stroop, word reading, errors Stroop, color reading, correct Stroop, color reading, errors
Post hoc p
28.9 (1.0)
27.8 (2.5)
15.4 (8.7)
47.16
c
4.3 (1.5) 2.0 (1.5) 0.1 (0.3)
4.7 (1.7) 3.2 (3.1) 0.3 (0.7)
7.5 (1.3) 7.0 (3.9) 2.0 (2.2)
4.54 4.49 9.81
c
0.3 (1.1) 0.5 (0.9) 0.0 (0.0) 0.5 (0.5) 0.4 (0.2) 0.0 (0.0) 0.0 (0.2) 0.2 (0.4) 0.1 (0.3) 8.3 (3.4) 3.1 (1.8) 18.6 (5.3) 6.3 (2.4) 38.7 (14.3) 1.6 (2.5) 25.1 (7.2) 0.1 (0.3) 6.8 (3.6) 0.1 (0.3) 21.7 (9.7) 0.0 (0.2) 43.2 (21.0) 0.5 (0.7) 111.5 (1.6) 0.2 (0.4) 95.5 (19.9) 2.7 (3.8)
0.1 (0.4) 0.5 (0.6) 0.0 (0.0) 0.6 (0.6) 0.2 (0.4) 0.2 (0.4) 0.3 (0.5) 0.5 (0.8) 0.3 (0.7) 10.9 (6.4) 4.0 (2.2) 14.6 (5.2) 5.1 (1.7) 29.6 (18.6) 1.4 (1.8) 22.1 (9.4) 0.1 (0.3) 10.8 (7.5) 0.2 (0.5) 64.0 (37.3) 0.3 (0.6) 142.2 (87.5) 1.4 (1.8) 104.3 (13.8) 0.9 (2.0) 78.3 (27.7) 2.9 (4.8)
0.3 (0.5) 2.0 (1.4) 0.0 (0.0) 1.0 (0.8) 4.3 (2.1) 1.8 (1.7) 1.8 (1.5) 2.0 (2.2) 0.5 (1.0) 27.8 (5.7) 7.3 (1.2) 7.3 (2.3) 3.7 (1.5) 10.0 (5.6) 1.3 (1.5) 8.7 (3.1) 0.3 (0.6) 15.0 (13.7) 11.0 (18.2) 147.5 (88.3) 0.5 (0.7) 150.0 1.8 28.5 (22.0) 1.5 (0.7) 27.5 (13.4) 5.5 (4.9)
1.12 6.68
0.332 c
0.33 104.43 20.71 19.10 7.43 0.58 20.46 6.26 8.38 3.09 6.01 0.07 6.03 0.72 3.17 19.16 34.04 1.76 21.78 2.56 69.91 1.77 11.45 0.21
0.718 b>c a > b, c a>b>c a>b>c
Scores in parentheses represent standard deviation. Analysis of cognitive function was performed using ANCOVA with age and education adjustment. a = Control; b = CADASIL-ND; c = CADASIL-D. * p < 0.05; ** p < 0.01; *** p < 0.001.
Discussion
We found that executive dysfunction and slow processing speed were apparent even in patients without dementia (CADASIL-ND group), suggesting that CADASIL manifests as frontal lobe dysfunction in the early stage. To our knowledge, this is the first study on cognitive decline of CADASIL in a non-Caucasian population. The earliest sign of CADASIL is impairment in the executive function and processing speed. The study of Pe220
Eur Neurol 2014;71:217–222 DOI: 10.1159/000356199
ters et al. [5] compared the cognitive function of patients with CADASIL and controls, and then compared the cognitive function between patients with no or mild impairment and those with advanced deficit. Patients with no or mild impairment performed poorer than controls in executive function, attention, and motor control. In our study, the CADASIL-ND group showed considerable decline in the executive function, attention, memory and motor control compared to matched controls. Thus, this pattern of cognitive deficit is consistent with the findings Song/Noh/Lee
Table 3. Distribution of major cardiovascular risk factors
Variable
Controls (n = 26)
CADASIL-ND (n = 52)
p
Hypertension Diabetes Hypercholesterolemia
10 (38.5) 2 (7.7) 3 (11.5)
23 (44.2) 6 (11.5) 10 (19.2)
0.627 0.712 0.526
Figures in parentheses indicate percentages.
Table 4. Influence of MRI markers on neuropsychological evalua-
tion in the CADASIL-ND group Cognitive measures
Independent variables
β standard
p value
MMSE
Age Education Lacunes nWMHs Age Education Lacunes nWMHs Age Education Lacunes nWMHs Age Education Lacunes nWMHs
–0.026 0.633 –0.13 0.047 0.055 –0.475 0.382 0.203 –0.201 0.445 –0.136 0.18 0.026 0.604 –0.237 –0.181
0.905
