Different aspects of dysexecutive syndrome in patients with moyamoya disease and its clinical subtypes

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OBJECTIVE

Dysexecutive syndrome is common in patients with moyamoya disease (MMD), a chronic cerebrovascular disease that is characterized by stenosis of the bilateral internal carotid arteries and progressive collateral revascularization, and MMD can be classified as ischemic or hemorrhagic according to the disease presentation and history. In this study, the authors aimed to determine which aspects of executive function are impaired in patients with MMD, in addition to the specific dysexecutive functions present among its clinical subtypes and the mechanisms underlying dysexecutive function in these patients.

METHODS

The authors administered 5 typical executive function tests (the Stroop test, the Hayling Sentence Completion Test [HSCT], the verbal fluency [VF] test, the N-back test, and the Sustained Attention to Response Task [SART]) to 49 patients with MMD and 47 IQ-, age-, education-, and social status–matched healthy controls. The dysexecutive questionnaire (DEX) was also used to assess participants' subjective feelings about their executive function. A total of 39 of the patients were evaluated by CT perfusion (CTP) before the assessments were performed, and the correlations among the performances of the patients on the above tests with the parameters of cerebral blood volume, cerebral blood flow (CBF), mean transit time (MTT), and time-to-peak (TTP) in the frontal lobes of these patients were also analyzed.

RESULTS

Many aspects of executive function in the patients with MMD were significantly poorer than those in the healthy controls, and the patients performed particularly poorer on the VF test, HSCT, N-back test, and SART. The patients with hemorrhagic MMD exhibited worse executive inhibition, executive processing, and semantic inhibition compared with those with ischemic MMD, but the latter group presented a worse working memory and poorer sustained attention. There were no significant differences in the DEX scores between the patients with MMD and healthy controls. The other findings were as follows: CBF was significantly positively correlated with the number correct on part B of the HSCT (r = 0.481, p = 0.01) and accuracy on the 0-back task of the N-back (r = 0.346, p = 0.031); MTT was significantly positively correlated with accuracy on the 2-back task of the N-back (r = 0.349, p = 0.034) and factor 5 of the DEX (r = 0.359, p = 0.032); and TTP was significantly positively correlated with the number correct on part B of the HSCT (r = 0.402, p = 0.034) and the 1-back reaction time of the N-back (r = 0.356, p = 0.026).

CONCLUSIONS

The patients with MMD exhibited impairments in semantic inhibition, executive processing, working memory, and sustained attention, but they were not aware of these deficits. Moreover, differences in dysexecutive function existed between the different subtypes of MMD. Hypoperfusion of the frontal lobe may be related to working memory and semantic inhibition impairments in patients with MMD.

ABBREVIATIONSCBF = cerebral blood flow; CBV = cerebral blood volume; CTP = CT perfusion; DEX = dysexecutive questionnaire; HSCT = Hayling Sentence Completion Test; ICA = internal carotid artery; MMD = moyamoya disease; MTT = mean transit time; ROI = region of interest; RT = reaction time; SART = Sustained Attention to Response Task; TIA = transient ischemic attack; TTP = time-to-peak; VF = verbal fluency.

OBJECTIVE

Dysexecutive syndrome is common in patients with moyamoya disease (MMD), a chronic cerebrovascular disease that is characterized by stenosis of the bilateral internal carotid arteries and progressive collateral revascularization, and MMD can be classified as ischemic or hemorrhagic according to the disease presentation and history. In this study, the authors aimed to determine which aspects of executive function are impaired in patients with MMD, in addition to the specific dysexecutive functions present among its clinical subtypes and the mechanisms underlying dysexecutive function in these patients.

METHODS

The authors administered 5 typical executive function tests (the Stroop test, the Hayling Sentence Completion Test [HSCT], the verbal fluency [VF] test, the N-back test, and the Sustained Attention to Response Task [SART]) to 49 patients with MMD and 47 IQ-, age-, education-, and social status–matched healthy controls. The dysexecutive questionnaire (DEX) was also used to assess participants' subjective feelings about their executive function. A total of 39 of the patients were evaluated by CT perfusion (CTP) before the assessments were performed, and the correlations among the performances of the patients on the above tests with the parameters of cerebral blood volume, cerebral blood flow (CBF), mean transit time (MTT), and time-to-peak (TTP) in the frontal lobes of these patients were also analyzed.

RESULTS

Many aspects of executive function in the patients with MMD were significantly poorer than those in the healthy controls, and the patients performed particularly poorer on the VF test, HSCT, N-back test, and SART. The patients with hemorrhagic MMD exhibited worse executive inhibition, executive processing, and semantic inhibition compared with those with ischemic MMD, but the latter group presented a worse working memory and poorer sustained attention. There were no significant differences in the DEX scores between the patients with MMD and healthy controls. The other findings were as follows: CBF was significantly positively correlated with the number correct on part B of the HSCT (r = 0.481, p = 0.01) and accuracy on the 0-back task of the N-back (r = 0.346, p = 0.031); MTT was significantly positively correlated with accuracy on the 2-back task of the N-back (r = 0.349, p = 0.034) and factor 5 of the DEX (r = 0.359, p = 0.032); and TTP was significantly positively correlated with the number correct on part B of the HSCT (r = 0.402, p = 0.034) and the 1-back reaction time of the N-back (r = 0.356, p = 0.026).

CONCLUSIONS

The patients with MMD exhibited impairments in semantic inhibition, executive processing, working memory, and sustained attention, but they were not aware of these deficits. Moreover, differences in dysexecutive function existed between the different subtypes of MMD. Hypoperfusion of the frontal lobe may be related to working memory and semantic inhibition impairments in patients with MMD.

Moyamoya disease (MMD) is a rare, chronic cerebrovascular disease characterized by bilateral progressive stenosis of the arteries of the circle of Willis, ultimately leading to occlusion of the distal intracranial internal carotid arteries (ICAs) and progressive collateral revascularization.2,13,16,21,32 MMD has variable clinical presentations. The disease causes ischemic stroke, intracranial hemorrhage, headache, seizures, and transient ischemic attacks (TIAs).27 MMD presentations can be subdivided into the following 4 categories, which are not mutually exclusive: ischemic, hemorrhagic, epileptic, and “other.”14 Hemorrhagic and ischemic MMD exhibit some differences. Hemorrhaging in patients with MMD is related to the fragility of the neovessels, and inadequate perfusion leads to ischemic presentations, which are classified as infarction, TIA, and “other.”21 Revascularization surgery is effective for improving symptoms and reducing the incidence of subsequent ischemic stroke in patients with ischemic MMD.23 Whether revascularization surgery is helpful for preventing future intracranial hemorrhaging remains unclear.17 Some studies have shown that patients who undergo revascularization surgery generally have a lower risk of rebleeding compared with those who undergo conservative treatment, but this difference is not statistically significant.11,17,23

Patients with MMD are known to exhibit impairments in some cognitive functions, especially executive functions.13,16,19,29,30,34 For example, Karzmark et al. assessed executive function in 30 patients with MMD by examining the total number of correct responses on the Delis-Kaplan Executive Functioning System Design Fluency Test, Letter and Category Fluency Tests, and part B of the Trail Making Test and found that some of these patients had impaired executive functioning.19 Notably, executive function is an umbrella term for cognitive processes, including inhibition, working memory, reasoning, task flexibility, problem solving, and planning and execution.9,12,25 The aspects of executive function that are impaired in patients with MMD are unknown. Furthermore, whether different clinical subtypes of MMD are associated with different types of dysexecutive function remains unclear. Moreover, the mechanisms underlying the dysexecutive function observed in patients with MMD remain unknown. Although studies have not obtained conclusive results in this regard, most studies have demonstrated that dysexecutive syndrome in patients with MMD is due to hypoperfusion.7,26,31 However, some researchers have suggested that there are other relevant risk factors or comorbid conditions that lead to dysexecutive syndrome, such as clinical stroke history, bilateral or unilateral disease, and younger age at onset.16,20,33 Therefore, a study of dysexecutive syndrome in different clinical MMD subtypes is warranted. Hence, in the current study, we aimed to determine which aspects of executive function are impaired in patients with MMD compared with healthy controls, and to identify the clinical subtypes and mechanisms underlying dysexecutive function in these patients.

Methods

Study Participants

We enrolled 56 patients in our study who were admitted to Beijing Tiantan Hospital at Capital Medical University in China from April 1, 2014, to September 15, 2014. All of the patients met the following inclusion criteria: 1) IQ > 70; 2) right-handed; 3) age > 10 years and < 50 years; 4) diagnosis of bilateral MMD based on digital subtraction angiography; 5) no history of revascularization surgery; 6) time interval from symptom onset to assessment of > 1 month; 7) ischemic MMD based on MRI results without intracranial bleeding prior to the assessment, and presentation as infarction, TIA, epilepsy, or other; and 8) hemorrhagic MMD with hemorrhagic presentation and a stable condition upon enrollment. The exclusion criteria were as follows: 1) diagnosis of psychological or mental disease; 2) other brain lesions, such as a brain tumor or brain trauma; 3) serious systemic disease, such as cardiac disease; and 4) severe dyskinesia or a language disorder that would prevent the completion of all of the tests. We also enrolled 4 patients who were diagnosed based on MR angiography, performed at an outpatient department. Additionally, we recruited 65 IQ-, age-, education-, social status- and sex-matched volunteers who had not been diagnosed with MMD or any other cerebral disease as the healthy control cohort. After exclusion of some of the subjects who had low intelligence (IQ < 70) or a high education level and those who did not complete all of the tests, a total of 47 healthy subjects and 49 patients were enrolled. Table 1 shows the patient demographics and clinical information.

TABLE 1.

Characteristics of participants and clinical information on patients

VariableMMD PatientsHealthy Controlst-Test/Chi-Square Testp Value
No. of cases4947
Mean age ± SD (yrs)27.88 ± 14.06327.21 ± 14.709−0.2260.821
Sex0.0450.831
  Male2422
  Female2525
Social Status1.0270.311
  City2125
  Noncity (county village)2822
Mean yrs of education ± SD7.47 ± 3.7598.51 ± 4.6241.2130.228
Mean estimated IQ ± SD96.52 ± 18.064103.83 ± 21.4641.5850.117
Type of MMD
Hemorrhagic13
Ischemic36
  TIA14
  Infarction19
  Epilepsy*1
  Others§3
Mean age of onset ± SD (years)25.76 ± 14.952
Mean duration of disease ± SD (mos)19.35 ± 24.408

One patient's presentation was classified as both epilepsy and infarction.

Presentations for “others” included headache, dizziness, and neck stiffness in our patients. MRI resulted in a diagnosis of ischemia, not infarction.

Imaging Protocol

A General Electric LightSpeed VCT scanner was used for evaluation of 39 of the patients by CT perfusion (CTP) before cognitive assessments. The mean time interval from CTP scanning to the assessments was 7 ± 3 days. Two neuroradiologists who were blinded to the clinical data jointly analyzed the CTP data using Neuro PCT software (Siemens Medical System) on a Siemens Medical System workstation. Maps of the cerebral blood volume (CBV) and cerebral blood flow (CBF), mean transit time (MTT), and time-to-peak (TTP) were generated as previously described.36 Four parameters were calculated from an average of 8 regions of interest (ROIs) in 2 layers located in frontal white matter with a normal appearance. We modified the ROIs that were selected as previously described.7 Each ROI consisted of a circle of 55–60 mm2.

Neuropsychological Tests

General Intelligence Test

All participants underwent an IQ evaluation using the Wechsler Adult Intelligence Scale-Third Edition (Chinese version) based on 4 subtests (Information, Digital Span, Similarity, and Arithmetic) or the Wechsler Intelligence Scale for Children-Fourth Edition (Chinese version) for those who were between 6 and 16 years of age.15,35

Executive Function Tests

Comprehensive executive function tests were performed to assess different aspects of executive function, including executive inhibition, semantic inhibition, executive processing, working memory, and sustained attention.

The Stroop test was used to assess executive inhibition.24 Participants were asked to select colors in the following 3 presentation formats: dots, words, and colors. The total time and number of mistakes were then recorded for each condition.

The Hayling Sentence Completion Test (HSCT) was employed to assess semantic inhibition.3 Participants were asked to complete a sentence with the final word omitted, in either a logical (Part A, initiation section) or illogical manner (Part B, inhibition section). In Part B, any word that is semantically associated with the sentence should be avoided. A shorter latency period and fewer errors on Part A or Part B indicate good initiation or inhibition function. For both Parts A and B, the total time (sum of all terms' reaction times [RTs]), correct number, and mean correct RT (total correct terms' RTs/correct number) were recorded. The numbers of type A and type B errors were also recorded for Part B.

The verbal fluency (VF) test was used to assess executive processing based on the number of words that were verbally produced in response to an animal's name within 1 minute.18 The total number and repeat number of the animal names were recorded.

The N-back test was used to assess the spatial working memory of each participant.4 Using computer software, a square and a plus sign (“+”) were presented on the screen, and their relative locations were varied; 0-back, 1-back, and 2-back tasks were used in the current study. The 0-back task required the participants to determine the various relative locations of 2 figures. The 1-back task required the subjects to keep the initial relative locations of the square and “+” in mind and to determine whether the next locations presented were different. The 2-back task was more difficult. For this task, participants were required to compare the relative locations of the square and “+” between the current trial and the trial before the last. For each trial, the accuracy and mean RT were recorded each time the mouse was pressed.

The Sustained Attention to Response Task (SART) was administered to assess the sustained attention of each subject.8,28 The SART is a computer test in which 225 single digits are presented to the test taker over 4.3 minutes. Each digit is presented for 250 msec, followed by a 900-msec mask. The participants were required to press a key in response to the digits except on 25 occasions, when the digit 3 would randomly appear. We recorded the following results: hits (the accuracy with which the participant pressed the mouse when a number other than 3 appeared), the hit RT (the mean RT of the hit), and the correct rejections (the accuracy with which the participant did not press the mouse when the number 3 appeared).

Dysexecutive Questionnaire

The Dysexecutive Questionnaire (DEX) was used to assess all of the participants' subjective feelings about their executive functioning. There were a total of 20 items, and this test was administered to participants aged 18 to 50. For the participants who were younger than 18 years of age, their families were required to complete these items using the DEX-other.10

Testing Procedure

After signing an informed consent form, each participant was evaluated using the above tests, with a random sequence of test administration, which did not affect the results of any of the tests. We expressed our appreciation to each participant for his or her involvement in the study. This study was approved by the Institutional Review Board of Beijing Tiantan Hospital in affiliation with Capital Medical University.

Statistical Analysis

A multivariate ANOVA was used to compare cognitive function between the patients with MMD and the healthy controls, patients with hemorrhagic MMD and ischemic MMD, as well as between 3 different ischemic presentations (infarction, TIA, and other). Because there was only 1 patient with epilepsy, which coexisted with infarction, we did not address this presentation. Moreover, age and education were used as covariates in the multivariate ANOVA. We also performed correlation analysis to assess the correlations of CBF, CBV, MTT, TTP, and the time interval from presentation to assessment with all of the test items. The level of statistical significance was set at 0.05.

Results

Differences in Test Performances Between Patients With MMD and Healthy Controls

A summary of the patients' test performances is provided in Table 2. The total number on the VF test was significantly lower for the patients with MMD than that for the healthy controls (F [1, 94] = 20.150, p < 0.05), indicating that the patients had poorer executive processing. The total time (F [1,94] = 11.222, p < 0.05, for part A; F [1,94] = 10.155, p < 0.05, for part B), mean correct RTs for both part A and part B (F [1,94] = 6.860, p < 0.05, and F [1,94] = 7.952, p < 0.05, respectively), and the number correct for part B of the HSCT (F [1,94] = 38.898, p < 0.05) were all significantly different between the patients with MMD and healthy controls, suggesting that the semantic inhibition of the patients with MMD was significantly worse compared with that of the healthy controls. The accuracy scores of the patients with MMD did not significantly differ from those of the controls on the 0-back and 1-back tasks of the N-back test (F [1,94] = 0.368, p > 0.05, and F [1,94] = 2.537, p > 0.05, respectively); however, the accuracy of these 2 groups significantly differed on the 2-back task (F [1,94] = 8.877, p < 0.05), indicating that the working memory of the patients with MMD was significantly poorer than that of the healthy controls when the difficulty of the test was increased.

TABLE 2.

Performances of patients with MMD and healthy controls on executive function tests

TestsPatients*Controls*F Valuep Value
Stroop1.6030.156
  Dot condition
     Total time20.348 ± 9.01816.05 ± 6.6227.0220.010
    No. of errors0.90 ± 1.3580.56 ± 0.9761.4280.235
  Word condition
    Total time (sec)26.262 ± 14.72420.288 ± 8.5065.6670.019
    No. of errors0.84 ± 1.2970.71 ± 1.3420.2130.646
  Color condition
    Total time (sec)41.624 ± 19.30931.265 ± 14.7576.8120.011
    No. of errors3.65 ± 3.4612.61 ± 3.1141.4460.232
VF test7.768<0.001
    Total no.13.63 ± 4.97818.93 ± 6.94820.150<0.001
    Repeat no.0.94 ± 1.1801.71 ± 3.7831.5830.212
HSCT4.306<0.001
  Part A
    Total time (sec)46.72 ± 25.83125.02 ± 11.20011.2220.001
    No. correct14.47 ± 1.2114.77 ± 0.6790.3320.567
    Mean correct RT (sec)3.40 ± 2.5471.73 ± 0.9256.8600.011
  Part B
    Total time (sec)98.41 ± 49.7353.79 ± 28.87710.1550.002
    No. correct3.21 ± 2.9426.73 ± 4.17738.8980.004
    No. Type A errors5.85 ± 2.8193.67 ± 3.5173.5310.065
    No. Type B errors5.91 ± 2.2614.63 ± 2.4423.1960.079
    Mean correct RT (sec)6.00 ± 4.2173.29 ± 2.0347.9520.006
N-back test2.9800.012
  0-back
    RT (msec)554.81 ± 112.175475.09 ± 83.0834.7990.031
    Accuracy0.92 ± 0.1210.94 ± 0.1300.3680.546
  1-back
    RT (msec)772.20 ± 249.823751.30 ± 223.0630.0170.896
    Accuracy0.55 ± 0.2150.66 ± 0.2292.5370.115
  2-back
    RT (msec)749.29 ± 327.278828.25 ± 312.8400.9610.330
    Accuracy0.35 ± 0.1590.49 ± 0.2258.8770.004
SART7.735<0.001
  Hit0.868 ± 0.1850.975 ± 0.0329.7740.002
  Hit RT (msec)483.248 ± 123.374397.784 ± 107.0128.6410.004
  Correct rejections0.67 ± 0.2150.81 ± 0.2246.8320.011

Data given as mean ± SD.

In addition, the RTs for the 0-back task (F [1, 94] = 4.799, p < 0.05), as well as hits (F [1, 94] = 9.774, p < 0.05) and the hit RT on the SART (F [1, 94] = 8.641, p < 0.05) significantly differed between the patients with MMD and healthy controls, suggesting that these patients had poorer sustained attention. However, none of the DEX questionnaire indices were significantly different.

Differences in Dysexecutive Function Among the Different Clinical Subtypes

The performances on all of the executive function tests were compared between the patients with hemorrhagic MMD and ischemic MMD (Table 3). The patients with hemorrhagic MMD exhibited poorer performances than the patients with ischemic MMD on the Stroop test, VF test, and HSCT, with the exception of the number of type A errors. However, the patients with hemorrhagic MMD performed better than the patients with ischemic MMD on the N-back test and SART, with the exception of the hit RT.

TABLE 3.

Performances on executive function tests between patients with hemorrhagic MMD and ischemic MMD

TestHemorrhagic Group*Ischemic Group*F Valuep Value
No. of patients1336
Stroop0.2390.961
  Dot condition
    Total time (sec)20.859 ± 8.99020.164 ± 9.1480.1430.708
    No. of errors1.00 ± 1.4720.86 ± 1.3340.7200.401
  Word condition
    Total time (sec)27.298 ± 13.37625.889 ± 15.3450.3180.576
    No. of errors0.77 ± 0.9270.86 ± 1.4170.1250.725
  Color condition1.6540.191
    Total time (sec)43.549 ± 19.62840.930 ± 19.4260.0840.773
    No. of errors3.62 ± 3.1763.67 ± 3.6020.0030.959
VF
  Total no.13.69 ± 3.17213.61 ± 5.5250.0040.950
  Repeat no.1.62 ± 1.5020.69 ± 0.9514.9290.031
HSCT1.4870.216
  Part A
    Total time (sec)52.22 ± 22.23444.43 ± 27.3002.4360.706
    No. correct14.30 ± 1.16014.54 ± 1.2500.2620.903
    Mean correct RT (sec)3.758 ± 1.9943.251 ± 2.7711.6590.564
  Part B
    Total time (sec)97.170 ± 53.23098.926 ± 49.38610.2340.113
    No. correct3.10 ± 1.5243.25 ± 3.3911.2960.907
    No. Type A errors5.30 ± 2.6276.08 ± 2.9180.9000.299
    No. Type B errors6.50 ± 1.9005.67 ± 2.3900.1130.304
    Mean correct RT (sec)6.051 ± 5.2195.978 ± 3.8540.0130.059
N-back0.7240.633
  0-back
    RT (msec)551.944 ± 103.249555.970 ± 117.1700.4100.526
    Accuracy0.923 ± 0.1090.921 ± 0.1230.4770.494
  1-back
    RT (msec)759.514 ± 272.308777.348 ± 244.5111.5980.213
    Accuracy0.562 ± 0.2430.550 ± 0.2060.0250.875
  2-back
    RT (msec)631.397 ± 344.694797.180 ± 312.7943.7770.059
    Accuracy0.356 ± 0.1660.345 ± 0.1580.0650.800
SART1.4120.235
  Hit0.854 ± 0.1620.873 ± 0.1940.0090.923
  Hit RT (msec)481.411 ± 125.627483.859 ± 124.4120.8640.358
  Correct rejections0.53 ± 0.2240.72 ± 0.1926.5350.014

Data given as mean ± SD.

Statistically significant.

There were no significant differences in test performances among the 3 ischemic subgroups (Table 4); however, the patients with infraction (subgroup 1) performed worse than those with TIA (subgroup 2), who performed worse than those in the “other” subgroup (subgroup 3), according to the results of the Stroop and VF tests. However, on the N-back test and SART, the patients in subgroup 1 performed more poorly than those in subgroup 3, who performed better than those in subgroup 2.

TABLE 4.

Executive function performances of the patients with MMD and ischemic presentations of infarction, TIA, and other

TestsInfarction (n = 19)*TIA (n = 14)*Other (n = 3)F Valuep Value
Stroop1.0250.440
  Dot condition
    Total time (sec)21.63 ± 11.33119.63 ± 5.69613.36 ± 2.4821.8190.179
    No. of errors1.05 ± 1.6150.79 ± 0.9750.000 ± 0.0001.4650.247
  Word condition
    Total time (sec)29.444 ± 18.54923.687 ± 9.94213.643 ± 1.6253.5260.042
    No. of errors1.00 ± 1.7320.86 ± 1.7320.00 ± .00±11.2580.298
  Color condition
    Total time (sec)48.43 ± 21.9334.89 ± 11.94121.66 ± 1.4395.8940.007
    No. of errors4.05 ± 4.1163.71 ± 4.1161.00 ± 4.1160.7820.466
VF0.9960.437
    Total no.12.58 ± 5.36814.36 ± 5.36816.67 ± 5.3682.1700.131
    Repeat no.0.74 ± 0.9910.71 ± 0.9910.33 ± 0.9910.1950.824
HSCT0.8520.613
  Part A
    Total time (sec)42.557 ± 28.35940.589 ± 23.39263.417 ± 36.4750.8950.424
    No. correct14.33 ± 1.72314.78 ± 0.44114.67 ± 0.5770.3610.702
    Mean correct RT (sec)3.340 ± 3.5092.751 ± 1.5864.394 ± 2.7170.4470.646
  Part B
    Total time (sec)102.37 ± 53.19685.415 ± 47.632125.65 ± 38.0081.2890.297
    No. correct2.83 ± 3.0704.00 ± 4.3012.67 ± 1.5280.4550.641
    No. Type A errors6.33 ± 2.9645.22 ± 3.0737.67 ± 2.0820.9950.387
    No. Type B errors5.83 ± 2.2905.78 ± 2.9494.67 ± 0.5770.2720.765
    Mean correct RT (sec)6.229 ± 4.3114.421 ± 2.8699.649 ± 2.0452.2940.127
N-back0.8840.568
  0-back
    RT (msec)613.436 ± 133.88507.809 ± 114.328571.810 ± 76.6722.7010.083
    Accuracy0.870 ± 0.1830.920 ± 0.0900.990 ± 0.0171.2470.301
  1-back
    RT (msec)830.872 ± 236.056684.761 ± 226.322944.177 ± 39.0050.6830.513
    Accuracy0.50 ± 0.1820.58 ± 0.2100.71 ± 0.1402.7420.078
  2-back
    RT (msec)808.361 ± 338.161754.470 ± 274.577922.630 ± 412.3770.3050.740
    Accuracy0.335 ± 0.1530.377 ± 0.1770.267 ± 0.0851.0390.367
SART0.7320.715
  Hit0.827 ± 0.2540.935 ± 0.0670.887 ± 0.0681.2260.307
  Hit RT (msec)513.482 ± 102.683437.808 ± 144.507511.150 ± 126.2711.9840.155
  Correct rejections0.703 ± 0.2120.732 ± 0.1810.803 ± 0.1101.0340.368

Data given as mean ± SD.

Statistically significant.

We also found that the patient age at onset was significantly negatively associated with the number of mistakes on the words condition of the Stroop test (r = −0.326, p = 0.022), and it was positively associated with the 1-back RT (r = 0.336, p = 0.018). The time interval from symptom onset to assessment (mean 19.35 ± 24.408 months) was also significantly negatively associated with the accuracy of the 1-back task (r = −0.432, p = 0.002) and the number of type B errors (r = −0.324, p = 0.03) and positively associated with the number correct (r = 0.412, p = 0.005) on part B of the HSCT.

Correlations Among CTP, the Time Interval From Presentation to Assessment, and Executive Function

CBF was significantly correlated with the number correct on part B of the HSCT (r = 0.481, p = 0.01) and accuracy on the 0-back task of the N-back (r = 0.346, p = 0.031). MTT was also significantly associated with accuracy on the 2-back task of the N-back (r = 0.349, p = 0.034) and factor 5 of the DEX (r = 0.359, p = 0.032), and TTP was significantly correlated with the number correct on part B of the HSCT (r = 0.402, p = 0.034) and the 1-back RT of the N-back (r = 0.356, p = 0.026).

Discussion

The results of the current study indicated that the patients with MMD had poorer executive functioning than the healthy controls, which is consistent with previous studies.6,7,13,26,31 We also found that various aspects of executive function, including semantic inhibition, executive processing, working memory, and sustained attention were significantly impaired in the patients. Moreover, the 2-back RTs in the patients with MMD were greater than that of the healthy controls, indicating that the controls spent more time thinking about how to achieve accuracy. Additionally, we found that most of the healthy controls consistently applied a strategy, for example, they used objects that they saw in the room as their answers to part B of the HSCT. However, almost all of the patients with MMD failed to employ a strategy for part B of the HSCT. Thus, patients with MMD may exhibit poorer executive processing and task flexibility.

Unfortunately, the results of the DEX questionnaire did not reflect this impairment in executive functioning and task flexibility, which suggested that the patients with MMD or their families did not recognize their dysexecutive syndrome, which may have led to a delayed visit to the clinic. A previous study has suggested that patients with MMD exhibit impaired metacognitive executive functioning.33 Moreover, the impairments in working memory and semantic inhibition that were observed in the patients with MMD in this study were significantly positively associated with the time interval between presentation and assessment, indicating a delayed a visit to the clinic, which may have led to worsened executive functioning, particularly working memory and semantic inhibition. A previous study has also suggested that a prolonged duration of symptoms and a younger age at onset are associated with cognitive impairment.16

Patients with MMD with different presentations exhibited differences in executive impairment, according to their results on tests administered in this study. Three highlights in our results should be addressed. First, our results showed that the patients with hemorrhagic MMD had poorer executive inhibition, executive processing, and semantic inhibition than the patients with ischemic MMD, but the latter group exhibited worse working memory and poorer sustained attention. Hemorrhage related to the fragility of the neovessels is an acute process, leading to much more severe impairment of the normal brain compared with ischemia, which is a chronic process. Chronic processes include compression of neovessels that supply blood. Moreover, working memory and sustained attention are more vulnerable over time than executive inhibition, executive processing, and semantic inhibition, which are related to stable functioning. Second, in terms of executive inhibition and executive processing, the patients with infarction had poorer results than those with TIA, whose results were poorer than those of the patients in the “other” subgroup. However, the patients in subgroup 1 exhibited worse results than those in subgroup 3, whose results were better than those of the patients in subgroup 2 in terms of working memory and sustained attention. Third, we found that the time interval from presentation onset to assessment was negatively associated with working memory but positively associated with semantic inhibition, which may indicate that the natural progression of MMD may be associated with not only improvements in some aspects of executive function, but also worsening in other aspects. Further study is needed to clarify the effects of disease progression on executive function. Previous studies have indicated that revascularization surgery could improve the cognitive functioning of patients with MMD.5,22 However, determining when surgery should be performed and which aspect of executive function is altered in patients with different subtypes of MMD require additional research. Further postoperative testing of these patients should be performed to clarify these issues.

Hypoperfusion of the frontal lobe may lead to some aspects of executive impairment in patients with MMD, especially regarding semantic inhibition and working memory. The results concerning the correlation between CTP and test performance in the current study indicated that perfusion of the frontal lobe was negatively correlated with semantic inhibition and working memory. The patients with infarction (located in the frontal lobes of all of the patients in subgroup 1) exhibited the worst performances on all of the tests in the 3 ischemic subgroups. This finding suggested that more severe ischemia led to poorer executive functioning, which is partially consistent with the results of previous studies, indicating that dysexecutive function results from hypoperfusion.7,26 Many neuroimaging and lesion studies have identified the functions that are most often associated with particular regions of the prefrontal cortex, including the dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex.1 Moreover, both hemorrhagic and ischemic MMD always lead to occlusive bilateral ICAs, which are the most common arteries that supply blood to the frontal lobe.7,26 Other researchers have also suggested that cognitive impairment in patients with MMD may be attributed to stroke history or comorbid conditions. Su et al. have determined that smoking and Suzuki angiographic classification are clinical risk factors for cognitive impairment in patients with hemorrhagic MMD.31 Williams et al. have also suggested that stroke history and bilateral disease are risk factors.33

The current study has some limitations. First, our sample size was small, particularly the patients with presentations classified as “other.” Second, all of our patients came from a single center, so the sample representation may not be optimal. Third, additional neuroimaging to detect frontal lobe function should have been performed to explore the potential mechanisms of dysexecutive function. Fourth, we did not include patients with ischemic or hemorrhagic disease due to an etiology other than MMD in the control group, which was matched to the patient group in terms of age, education level, and social status.

In summary, the current study provided evidence of the specific dysexecutive syndrome present in patients with MMD and its potential relationships with hemorrhage and ischemic presentation. Furthermore, our findings shed light on the consequences of cognitive dysfunction in MMD and its clinical subtypes and the potential mechanisms of the underlying dysexecutive impairments. In the future, we will seek to determine whether surgical revascularization improves dysexecutive syndrome in patients with hemorrhagic and ischemic MMD, as well as the aspects of executive function that may be altered.

Conclusions

The patients with MMD exhibited poorer executive functioning, especially with regard to semantic inhibition, executive processing, working memory, and sustained attention. However, they did not report subjective feelings related to their dysexecutive syndrome. The patients with hemorrhagic MMD showed poorer executive inhibition, executive processing, and semantic inhibition than the patients with ischemic MMD, and the latter group showed worse working memory and poorer sustained attention. The patients with infarction exhibited the worst executive inhibition among the 3 subgroups of patients with ischemic MMD, and CTP of the frontal lobe was significantly correlated with perfusion of the frontal lobe, suggesting that chronic cerebral hypoperfusion results in impairments in the working memory and semantic inhibition aspects of dysexecutive function; however, this correlation may not fully explain other aspects of dysexecutive function.

Acknowledgments

Our study was supported by the National Natural Science Foundation of China (grant nos. 81172192 and 31100747) and the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (grant no. 2013BAI09B03).

References

  • 1

    Alvarez JAEmory E: Executive function and the frontal lobes: a meta-analytic review. Neuropsychol Rev 16:17422006

  • 2

    Araki YTakagi YUeda KUbukata SIshida JFunaki T: Cognitive function of patients with adult moyamoya disease. J Stroke Cerebrovasc Dis 23:178917942014

    • Search Google Scholar
    • Export Citation
  • 3

    Burgess PWVeitch Ede Lacy Costello AShallice T: The cognitive and neuroanatomical correlates of multitasking. Neuropsychologia 38:8488632000

    • Search Google Scholar
    • Export Citation
  • 4

    Callicott JHRamsey NFTallent KBertolino AKnable MBCoppola R: Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia. Neuropsychopharmacology 18:1861961998

    • Search Google Scholar
    • Export Citation
  • 5

    Calviere LCatalaa IMarlats FJanuel ACLagarrigue JLarrue V: Improvement in cognitive function and cerebral perfusion after bur hole surgery in an adult with moyamoya disease. Case report. J Neurosurg 115:3473492011

    • Search Google Scholar
    • Export Citation
  • 6

    Calviere LCatalaa IMarlats FViguier ABonneville FCognard C: Correlation between cognitive impairment and cerebral hemodynamic disturbances on perfusion magnetic resonance imaging in European adults with moyamoya disease. Clinical article. J Neurosurg 113:7537592010

    • Search Google Scholar
    • Export Citation
  • 7

    Calviere LSsi Yan Kai GCatalaa IMarlats FBonneville FLarrue V: Executive dysfunction in adults with moyamoya disease is associated with increased diffusion in frontal white matter. J Neurol Neurosurg Psychiatry 83:5915932012

    • Search Google Scholar
    • Export Citation
  • 8

    Chan RCChen EYCheung EFChen RYCheung HK: A study of sensitivity of the sustained attention to response task in patients with schizophrenia. Clin Neuropsychol 18:1141212004

    • Search Google Scholar
    • Export Citation
  • 9

    Chan RCShum DToulopoulou TChen EY: Assessment of executive functions: review of instruments and identification of critical issues. Arch Clin Neuropsychol 23:2012162008

    • Search Google Scholar
    • Export Citation
  • 10

    Chan RCK: Dysexecutive symptoms among a non-clinical samples: a study with the use of DEX. Br J Psychol 92:5515652001

  • 11

    Choi WSLee SBKim DSHuh PWYoo DSLee TG: Thirteen-year experience of 44 patients with adult hemorrhagic moyamoya disease from a single institution: clinical analysis by management modality. J Cerebrovasc Endovasc Neurosurg 15:1911992013

    • Search Google Scholar
    • Export Citation
  • 12

    Elliott R: Executive functions and their disorders. Br Med Bull 65:49592003

  • 13

    Festa JRSchwarz LRPliskin NCullum CMLacritz LCharbel FT: Neurocognitive dysfunction in adult moyamoya disease. J Neurol 257:8068152010

    • Search Google Scholar
    • Export Citation
  • 14

    Fukui M: Current state of study on moyamoya disease in Japan. Surg Neurol 47:1381431997

  • 15

    Gong Y: Wechsler Adult Intelligence Scale–Chinese Version Manual Changsha, ChinaChinese Map Press1992

  • 16

    Hsu YHKuo MFHua MSYang CC: Selective neuropsychological impairments and related clinical factors in children with moyamoya disease of the transient ischemic attack type. Childs Nerv Syst 30:4414472014

    • Search Google Scholar
    • Export Citation
  • 17

    Ikezaki KFukui MInamura TKinukawa NWakai KOno Y: The current status of the treatment for hemorrhagic type moyamoya disease based on a 1995 nationwide survey in Japan. Clin Neurol Neurosurg 99:Suppl 2S183S1861997

    • Search Google Scholar
    • Export Citation
  • 18

    Johnson-Selfridge MTZalewski CAboudarham JF: The relationship between ethnicity and word fluency. Arch Clin Neuropsychol 13:3193251998

    • Search Google Scholar
    • Export Citation
  • 19

    Karzmark PZeifert PDBell-Stephens TESteinberg GKDorfman LJ: Neurocognitive impairment in adults with moyamoya disease without stroke. Neurosurgery 70:6346382012

    • Search Google Scholar
    • Export Citation
  • 20

    Kossorotoff M: Cognitive decline in moyamoya: influence of chronic cerebral hypoxia, history of stroke, or comorbid conditions?. Dev Med Child Neurol 54:562012

    • Search Google Scholar
    • Export Citation
  • 21

    Kuroda SHoukin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:105610662008

  • 22

    Lee JYPhi JHWang KCCho BKShin MSKim SK: Neurocognitive profiles of children with moyamoya disease before and after surgical intervention. Cerebrovasc Dis 31:2302372011

    • Search Google Scholar
    • Export Citation
  • 23

    Lee SBKim DSHuh PWYoo DSLee TGCho KS: Long-term follow-up results in 142 adult patients with moyamoya disease according to management modality. Acta Neurochir (Wien) 154:117911872012

    • Search Google Scholar
    • Export Citation
  • 24

    Lee TMChan CC: Stroop interference in Chinese and English. J Clin Exp Neuropsychol 22:4654712000

  • 25

    Monsell S: Task switching. Trends Cogn Sci 7:1341402003

  • 26

    Nakamizo AKikkawa YHiwatashi AMatsushima TSasaki T: Executive function and diffusion in frontal white matter of adults with moyamoya disease. J Stroke Cerebrovasc Dis 23:4574612014

    • Search Google Scholar
    • Export Citation
  • 27

    Parray TMartin TWSiddiqui S: Moyamoya disease: a review of the disease and anesthetic management. J Neurosurg Anesthesiol 23:1001092011

    • Search Google Scholar
    • Export Citation
  • 28

    Robertson IHManly TAndrade JBaddeley BTYiend J: ‘Oops!’: performance correlates of everyday attentional failures in traumatic brain injured and normal subjects. Neuropsychologia 35:7477581997

    • Search Google Scholar
    • Export Citation
  • 29

    Schwarz LRThurstin AHLevine LA: A single case report of Moyamoya disease presenting in a psychiatric setting. Appl Neuropsychol 17:73772010

    • Search Google Scholar
    • Export Citation
  • 30

    Su SHHai JZhang LWu YFYu F: Quality of life and psychological impact in adult patients with hemorrhagic moyamoya disease who received no surgical revascularization. J Neurol Sci 328:32362013

    • Search Google Scholar
    • Export Citation
  • 31

    Su SHHai JZhang LYu FWu YF: Assessment of cognitive function in adult patients with hemorrhagic moyamoya disease who received no surgical revascularization. Eur J Neurol 20:108110872013

    • Search Google Scholar
    • Export Citation
  • 32

    Weinberg DGRahme RJAoun SGBatjer HHBendok BR: Moyamoya disease: functional and neurocognitive outcomes in the pediatric and adult populations. Neurosurg Focus 30:6E212011

    • Search Google Scholar
    • Export Citation
  • 33

    Williams TSWestmacott RDlamini NGranite LDirks PAskalan R: Intellectual ability and executive function in pediatric moyamoya vasculopathy. Dev Med Child Neurol 54:30372012

    • Search Google Scholar
    • Export Citation
  • 34

    Zalonis IChristidi FKararizou ETriantafyllou NISpengos KVassilopoulos D: Cognitive deficits presenting as psychiatric symptoms in a patient with Moyamoya disease. Psychol Rep 107:7277322010

    • Search Google Scholar
    • Export Citation
  • 35

    Zhang H: Wechesler Intelligence Scale for Children—Fourth Edition Chinese Version Manual Zhuhai, ChinaKing-May Psychological Assessment Technology Development, Ltd.2008

    • Search Google Scholar
    • Export Citation
  • 36

    Zhou JZhang HGao PLin YLi X: Assessment of perihematomal hypoperfusion injury in subacute and chronic intra-cerebral hemorrhage by CT perfusion imaging. Neurol Res 32:6426492010

    • Search Google Scholar
    • Export Citation

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Wan, Fang, Huang, Chan, Wang. Acquisition of data: Fang, Zhang, Chan. Analysis and interpretation of data: all authors. Drafting the article: Fang. Critically revising the article: Wan, Huang, Chan. Reviewed submitted version of manuscript: Wan, Huang, Wang. Statistical analysis: Zhang, Wang. Administrative/technical/material support: Wang. Study supervision: Wang.

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Article Information

INCLUDE WHEN CITING Published online January 1, 2016; DOI: 10.3171/2015.7.JNS142666.

Correspondence Weiqing Wan, No. 6 Tiantan Xili, Dongcheng District, Beijing 100050, People's Republic of China. email: weiqingwan111@163.com.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Alvarez JAEmory E: Executive function and the frontal lobes: a meta-analytic review. Neuropsychol Rev 16:17422006

  • 2

    Araki YTakagi YUeda KUbukata SIshida JFunaki T: Cognitive function of patients with adult moyamoya disease. J Stroke Cerebrovasc Dis 23:178917942014

    • Search Google Scholar
    • Export Citation
  • 3

    Burgess PWVeitch Ede Lacy Costello AShallice T: The cognitive and neuroanatomical correlates of multitasking. Neuropsychologia 38:8488632000

    • Search Google Scholar
    • Export Citation
  • 4

    Callicott JHRamsey NFTallent KBertolino AKnable MBCoppola R: Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia. Neuropsychopharmacology 18:1861961998

    • Search Google Scholar
    • Export Citation
  • 5

    Calviere LCatalaa IMarlats FJanuel ACLagarrigue JLarrue V: Improvement in cognitive function and cerebral perfusion after bur hole surgery in an adult with moyamoya disease. Case report. J Neurosurg 115:3473492011

    • Search Google Scholar
    • Export Citation
  • 6

    Calviere LCatalaa IMarlats FViguier ABonneville FCognard C: Correlation between cognitive impairment and cerebral hemodynamic disturbances on perfusion magnetic resonance imaging in European adults with moyamoya disease. Clinical article. J Neurosurg 113:7537592010

    • Search Google Scholar
    • Export Citation
  • 7

    Calviere LSsi Yan Kai GCatalaa IMarlats FBonneville FLarrue V: Executive dysfunction in adults with moyamoya disease is associated with increased diffusion in frontal white matter. J Neurol Neurosurg Psychiatry 83:5915932012

    • Search Google Scholar
    • Export Citation
  • 8

    Chan RCChen EYCheung EFChen RYCheung HK: A study of sensitivity of the sustained attention to response task in patients with schizophrenia. Clin Neuropsychol 18:1141212004

    • Search Google Scholar
    • Export Citation
  • 9

    Chan RCShum DToulopoulou TChen EY: Assessment of executive functions: review of instruments and identification of critical issues. Arch Clin Neuropsychol 23:2012162008

    • Search Google Scholar
    • Export Citation
  • 10

    Chan RCK: Dysexecutive symptoms among a non-clinical samples: a study with the use of DEX. Br J Psychol 92:5515652001

  • 11

    Choi WSLee SBKim DSHuh PWYoo DSLee TG: Thirteen-year experience of 44 patients with adult hemorrhagic moyamoya disease from a single institution: clinical analysis by management modality. J Cerebrovasc Endovasc Neurosurg 15:1911992013

    • Search Google Scholar
    • Export Citation
  • 12

    Elliott R: Executive functions and their disorders. Br Med Bull 65:49592003

  • 13

    Festa JRSchwarz LRPliskin NCullum CMLacritz LCharbel FT: Neurocognitive dysfunction in adult moyamoya disease. J Neurol 257:8068152010

    • Search Google Scholar
    • Export Citation
  • 14

    Fukui M: Current state of study on moyamoya disease in Japan. Surg Neurol 47:1381431997

  • 15

    Gong Y: Wechsler Adult Intelligence Scale–Chinese Version Manual Changsha, ChinaChinese Map Press1992

  • 16

    Hsu YHKuo MFHua MSYang CC: Selective neuropsychological impairments and related clinical factors in children with moyamoya disease of the transient ischemic attack type. Childs Nerv Syst 30:4414472014

    • Search Google Scholar
    • Export Citation
  • 17

    Ikezaki KFukui MInamura TKinukawa NWakai KOno Y: The current status of the treatment for hemorrhagic type moyamoya disease based on a 1995 nationwide survey in Japan. Clin Neurol Neurosurg 99:Suppl 2S183S1861997

    • Search Google Scholar
    • Export Citation
  • 18

    Johnson-Selfridge MTZalewski CAboudarham JF: The relationship between ethnicity and word fluency. Arch Clin Neuropsychol 13:3193251998

    • Search Google Scholar
    • Export Citation
  • 19

    Karzmark PZeifert PDBell-Stephens TESteinberg GKDorfman LJ: Neurocognitive impairment in adults with moyamoya disease without stroke. Neurosurgery 70:6346382012

    • Search Google Scholar
    • Export Citation
  • 20

    Kossorotoff M: Cognitive decline in moyamoya: influence of chronic cerebral hypoxia, history of stroke, or comorbid conditions?. Dev Med Child Neurol 54:562012

    • Search Google Scholar
    • Export Citation
  • 21

    Kuroda SHoukin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:105610662008

  • 22

    Lee JYPhi JHWang KCCho BKShin MSKim SK: Neurocognitive profiles of children with moyamoya disease before and after surgical intervention. Cerebrovasc Dis 31:2302372011

    • Search Google Scholar
    • Export Citation
  • 23

    Lee SBKim DSHuh PWYoo DSLee TGCho KS: Long-term follow-up results in 142 adult patients with moyamoya disease according to management modality. Acta Neurochir (Wien) 154:117911872012

    • Search Google Scholar
    • Export Citation
  • 24

    Lee TMChan CC: Stroop interference in Chinese and English. J Clin Exp Neuropsychol 22:4654712000

  • 25

    Monsell S: Task switching. Trends Cogn Sci 7:1341402003

  • 26

    Nakamizo AKikkawa YHiwatashi AMatsushima TSasaki T: Executive function and diffusion in frontal white matter of adults with moyamoya disease. J Stroke Cerebrovasc Dis 23:4574612014

    • Search Google Scholar
    • Export Citation
  • 27

    Parray TMartin TWSiddiqui S: Moyamoya disease: a review of the disease and anesthetic management. J Neurosurg Anesthesiol 23:1001092011

    • Search Google Scholar
    • Export Citation
  • 28

    Robertson IHManly TAndrade JBaddeley BTYiend J: ‘Oops!’: performance correlates of everyday attentional failures in traumatic brain injured and normal subjects. Neuropsychologia 35:7477581997

    • Search Google Scholar
    • Export Citation
  • 29

    Schwarz LRThurstin AHLevine LA: A single case report of Moyamoya disease presenting in a psychiatric setting. Appl Neuropsychol 17:73772010

    • Search Google Scholar
    • Export Citation
  • 30

    Su SHHai JZhang LWu YFYu F: Quality of life and psychological impact in adult patients with hemorrhagic moyamoya disease who received no surgical revascularization. J Neurol Sci 328:32362013

    • Search Google Scholar
    • Export Citation
  • 31

    Su SHHai JZhang LYu FWu YF: Assessment of cognitive function in adult patients with hemorrhagic moyamoya disease who received no surgical revascularization. Eur J Neurol 20:108110872013

    • Search Google Scholar
    • Export Citation
  • 32

    Weinberg DGRahme RJAoun SGBatjer HHBendok BR: Moyamoya disease: functional and neurocognitive outcomes in the pediatric and adult populations. Neurosurg Focus 30:6E212011

    • Search Google Scholar
    • Export Citation
  • 33

    Williams TSWestmacott RDlamini NGranite LDirks PAskalan R: Intellectual ability and executive function in pediatric moyamoya vasculopathy. Dev Med Child Neurol 54:30372012

    • Search Google Scholar
    • Export Citation
  • 34

    Zalonis IChristidi FKararizou ETriantafyllou NISpengos KVassilopoulos D: Cognitive deficits presenting as psychiatric symptoms in a patient with Moyamoya disease. Psychol Rep 107:7277322010

    • Search Google Scholar
    • Export Citation
  • 35

    Zhang H: Wechesler Intelligence Scale for Children—Fourth Edition Chinese Version Manual Zhuhai, ChinaKing-May Psychological Assessment Technology Development, Ltd.2008

    • Search Google Scholar
    • Export Citation
  • 36

    Zhou JZhang HGao PLin YLi X: Assessment of perihematomal hypoperfusion injury in subacute and chronic intra-cerebral hemorrhage by CT perfusion imaging. Neurol Res 32:6426492010

    • Search Google Scholar
    • Export Citation

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