Chronic ischemia alters brain microstructural integrity and cognitive performance in adult moyamoya...

354

Moyamoya disease (MMD) is characterized by the pres-ence of net-like collateral vessels at the brain base that

are caused by progressive major cerebral artery occlusion.1 Executive function/attention and working memory, primar-ily mediated by the lateral prefrontal region, are impaired, suggesting that lateral prefrontal ischemia is responsible for neurocognitive dysfunction.2,3 A recent investigation revealed the association of neurocognitive dysfunction with reduced cerebral blood flow.3 Nevertheless, not all patients with neu-rocognitive dysfunction had cerebral infarction on conven-tional MRI. Thus, ischemia-induced subtle microstructural alterations, which are beyond the detectability of conventional MRI, underlie neurocognitive dysfunction in MMD.

Subtle gray matter changes, not shown on conventional MRI, are successfully detected in many diseases, such as mild cognitive impairment and schizophrenia, through voxel-by-voxel comparison of gray matter density on 3-dimensional (3D) MRI.4,5 Diffusion tensor imaging (DTI) is reportedly highly sensitive to microstructural alterations in diffusion

characteristics of white matter.6–9 To the best of our knowl-edge, no reports have evaluated gray matter changes in MMD using 3D MRI. There are only few reports on DTI assess-ments of MMD white matter integrity.6–8 Nevertheless, these reports used a specified region-of-interest approach and evalu-ated only 2 major DTI indices, such as fractional anisotropy (FA) and mean diffusivity (MD). Voxel-based analysis of white matter can provide detailed topographical characteris-tics of white matter integrity, and tractography can show the integrity of the major white matter tracts that run in anatomic regions. Furthermore, additional information for character-izing chronic ischemia-induced white matter damage can be extracted by incorporating other major DTI indices, such as axial diffusivity (AD) and radial diffusivity (RD).

Here, we investigated the brain’s microstructure across dif-ferent regions in adult MMD by a voxel-based analysis of gray and white matter and tractography, and evaluated the relation-ship of these microstructural alterations with hemodynamic compromise and neurocognitive dysfunction.

Background and Purpose—The mechanisms underlying frontal lobe dysfunction in moyamoya disease (MMD) are unknown. We aimed to determine whether chronic ischemia induces subtle microstructural brain changes in adult MMD and evaluated the association of changes with neuropsychological performance.

Methods—MRI, including 3-dimensional T1-weighted imaging and diffusion tensor imaging, was performed in 23 adult patients with MMD and 23 age-matched controls and gray matter density and major diffusion tensor imaging indices were compared between them; any alterations in the patients were tested for associations with age, ischemic symptoms, hemodynamic compromise, and neuropsychological performance.

Results—Decrease in gray matter density, associated with hemodynamic compromise (P<0.05), was observed in the posterior cingulate cortex of patients with MMD. Widespread reduction in fractional anisotropy and increases in radial diffusivity and mean diffusivity in some areas were also observed in bilateral cerebral white matter. The fractional anisotropy (r=0.54; P<0.0001) and radial diffusivity (r=−0.41; P<0.01) of white matter significantly associated with gray matter density of the cingulate cortex. The mean fractional anisotropy of the white matter tracts of the lateral prefrontal, cingulate, and inferior parietal regions were significantly associated with processing speed, executive function/attention, and working memory.

Conclusions—In adult MMD, there were more white matter abnormalities than gray matter changes. Disruption of white matter may play a pivotal role in the development of cognitive dysfunction. (Stroke. 2015;46:354-360. DOI: 10.1161/STROKEAHA.114.007407.)

Key Words: diffusion ◼ ischemia ◼ magnetic resonance imaging ◼ moyamoya disease ◼ white matter disease

Chronic Ischemia Alters Brain Microstructural Integrity and Cognitive Performance in Adult Moyamoya Disease

Ken Kazumata, MD; Khin Khin Tha, MD; Hisashi Narita, MD; Ichiro Kusumi, MD; Hideo Shichinohe, MD; Masaki Ito, MD; Naoki Nakayama, MD; Kiyohiro Houkin, MD

Received September 10, 2014; final revision received November 5, 2014; accepted November 26, 2014.From the Departments of Neurosurgery (K.K., H.S., M.I., N.N., K.H.), Radiobiology and Medical Engineering (K.K.T.), and Psychiatry (H.N., I.K.),

Hokkaido University Graduate School of Medicine, Sapporo, Japan.The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.

114.007407/-/DC1.Correspondence to Ken Kazumata, MD, Department of Neurosurgery, Hokkaido University Graduate School of Medicine, N 15 W 7, Kita, Sapporo

060-8638, Japan. Email [email protected]© 2014 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.007407

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Kazumata et al Brain Microstructural Changes in Moyamoya Disease 355

Materials and MethodsParticipantsThis prospective study was approved by the Research Ethics Committee of Hokkaido University Hospital. Written informed con-sent was obtained from all participants.

The inclusion criteria were clinical diagnosis of idiopathic MMD according to the consensus criteria and guideline for MMD pro-posed by the Research Committee on Spontaneous Occlusion of the Circle of Willis and age of >20.10 The exclusion criteria were quasi-moyamoya syndrome with conditions such as Down syndrome and neurofibromatosis, cortical infarction or subcortical lesion of >8 mm in the largest dimension on conventional MRI, intracranial hemor-rhage, revascularization surgery before the study, apparent neurologi-cal deficit because of stroke, and comorbid illnesses that could affect cognition. After exclusions, 23 patients (6 men, 17 women, 21–58 years; mean age, 40.9±9.5 years) were enrolled. The selection period was 25 months (from April 2012 to April 2014).

The inclusion criteria for controls were no clinical evidence of psychiatric or neurological disorders, normal intelligence quotient as assessed by the Japanese version of the Nelson Adult Reading Test,11 no brain lesions on conventional MRI, and no medication that could affect cognitive function. The control group also comprised 23 sub-jects (10 men, 13 women; 25–56 years; mean age, 39.0±8.1 years). The mean estimated intelligence quotient was 108.3±6.6.

Hemodynamic Status AssessmentCerebrovascular reactivity assessed by single positron emission com-puted tomography was used to determine the hemodynamic status in patients with MMD. A cerebrovascular reactivity of <15% in the left- or right-middle cerebral artery territory was considered as a hemody-namic compromise. Single positron emission computed tomography was performed within 7 days from MRI in 18 patients (Appendix I in the online-only Data Supplement).

Neuropsychological AssessmentThe neuropsychological assessment was performed in all patients with MMD. A neuropsychological battery sensitive to cognitive dysfunction because of frontal lobe injury was used and comprised the Wechsler Adult Intelligent scale-III, Wisconsin Card Sorting test, Trail Making Test (TMT; parts A and B), continuous performance task, Stroop test, and reading span test. Details are provided elsewhere (Appendix II in the online-only Data Supplement). Neuropsychologists blinded to the clinical data performed the tests. The interval between the neuropsy-chological tests and MRI was <1 month.

MRI AnalysisMRI was performed on a 3.0-T imager (Achieva TX; Philips Medical Solutions, Best, The Netherlands). Three-dimensional magnetiza-tion–prepared rapid gradient-echo T1-weighted imaging and axial single-shot spin-echo echo-planar DTI were performed to evaluate subtle gray and white matter alterations. The scan parameters are de-tailed elsewhere (Appendix III in the online-only Data Supplement). In addition, axial fast spin-echo T2-weighted imaging and fluid-at-tenuated inversion recovery imaging were also performed in patients with MMD to rule out cortical and subcortical infarctions and evalu-ate white matter hyperintensities.

Image Processing and Evaluation

Identification of Gray Matter AlterationsThree-dimensional magnetization–prepared rapid gradient-echo im-ages were used to compare gray matter density voxel-by-voxel be-tween patients with MMD and controls. The steps for voxel-based morphometry of FSL (FSL-VBM, version 4.1, http://www.fmrib.ox.ac.uk/fsl) using default parameters were followed12,13 (Appendix IV in the online-only Data Supplement). Age was considered as a

covariate. A P<0.05 after correction for family-wise error was con-sidered statistically significant.

Identification of White Matter AlterationsTo identify subtle white matter alterations, the 4 major DTI indices (FA, MD, AD, and RD) were first extracted from the DTI using the Diffusion Toolbox of FSL and the default parameters.12–14 Correction for eddy current distortions and motion was performed before extract-ing the indices. Differences in the major DTI indices between patients with MMD and controls were then tested using tract-based spatial statistics, which is a part of FSL. The default parameters and steps recommended by the software developers were used (Appendix V in the online-only Data Supplement). Age was a covariate, and results were corrected for multiple comparisons across space using thresh-old-free cluster enhancement. For each major DTI index, the mean value and number of voxels reaching statistical significance (thresh-old-free cluster enhancement-corrected; P<0.05) were calculated.

Probabilistic tractography was performed using FLIRT and BEDPOSTX (Appendix VI in the online-only Data Supplement). Sixteen cortical regions and bilateral thalami, which mediate intel-ligence, working memory, executive function/attention were selected as the seed regions. The entire brain was selected as the target region. For each probabilistic tract, the number of voxels and mean FA value were calculated.

Correlation of Microstructural Alterations With Hemodynamic Compromise and Neurocognitive FunctionVoxels with abnormal gray matter density in patients with MMD were tested for correlation with the major DTI white matter indices. Any gray or white matter alterations were tested for correlation with age, presence of ischemic symptoms, hemodynamic compromise, and neuropsychological performance. Pearson product-moment correla-tion analysis (correlation with age, Wechsler Adult Intelligent scale-III, TMT A and B) or permutation tests performed >10 000× (presence of ischemic symptoms, hemodynamic compromise, Wisconsin Card Sorting Test, Stroop test, continuous performance task, and reading span test; a cutoff value was applied for the latter 4 tests) were used for these purposes. For all correlations or comparisons, a P<0.05 was considered statistically significant.

ResultsPatient CharacteristicsPatient characteristics are summarized in Table. There were no significant differences in age (P=0.47) and sex (P=0.35) between patients and controls. Cerebral blood flow at rest, cere-brovascular reactivity, and prevalence of comorbid risk factors did not vary significantly between the symptomatic (ie, tran-sient ischemic attack, n=10 and asymptomatic, n=13) patients. White matter hyperintensities were observed in 10 (43.5%) patients with MMD on T2-weighted or fluid-attenuated inver-sion recovery images. Hyperintensities were also more frequent in the symptomatic patients (7/10; P<0.05). The mean full-scale intelligence quotient of patients with MMD was 94±13. The neuropsychological assessment results of the patients are sum-marized in Table I in the online-only Data Supplement. There were no significant differences in the full-scale intelligence quotient or scores of other Wechsler Adult Intelligent scale indices or other components of the neuropsychological battery between symptomatic and asymptomatic patients.

Gray Matter AlterationsFSL-VBM revealed a significant reduction in the density of the bilateral posterior cingulate cortex (PCC; Figure 1).

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356 Stroke February 2015

White Matter AlterationsTract-based spatial statistics showed a significant widespread FA decrease and RD increase in patients with MMD, (55.2% and 42.5%, respectively, of the entire skeleton; Figure 2). Some voxels with FA and RD alterations also revealed signifi-cant MD increases. Voxels showing MD increases occupied 20.9% of the mean FA skeleton. Regarding AD, no voxels sur-vived after correction for multiple comparisons, although AD decreases were observed mainly at the superior longitudinal fasciculus and cingulate bundle when correction was not per-formed (uncorrected P<0.05).

Probabilistic tractography also revealed decreases in the mean FA of several white matter tracts in patients with MMD. The number of voxels of each tract of patients with MMD did not vary significantly from that of controls.

Correlation of Microstructural Alterations With Hemodynamic Compromise and Neurocognitive FunctionThe density of the cingulate cortex of the patients signifi-cantly correlated with the mean FA (r=0.54; P<0.0001) or RD (r=−0.41; P<0.01) of the white matter skeleton (Figure 3).

The density of the bilateral PCC (http://fmri.wfubmc.edu/software/PickAtlas) and the mean FA of the white matter skel-eton of patients with MMD had inverse associations with age (r=−0.43; P<0.01 and r=−0.57; P<0.005, respectively; Figure I in the online-only Data Supplement). The local gray mat-ter density or major DTI indices did not vary significantly between symptomatic and asymptomatic patients. Patients with hemodynamic compromise had significantly lower PCC densities than their counterparts, but the means of each major DTI index of the white matter skeleton did not vary between these 2 groups.

Both the PCC density and mean values of the major DTI indices of the white matter skeleton were not significantly associated with neuropsychological performance. However, the mean FA of the following white matter tracts significantly associated with neuropsychological performance (Table II in the online-only Data Supplement; Figure 4); the fibers origi-nating from the left superior frontal with the processing speed (r=0.45); left middle frontal, left supramarginal gyrus, and right supramarginal gyrus with TMT A (r=0.43, 0.43, and 0.48, respectively); and left PCC with TMT B and A (r=0.43). The mean FA values of the tracts originating from the right

Table. Patient Characteristics

Sex Age, yClinical

Presentation Location of WMH

Suzuki Grade Hemodynamic Compromise

Comorbid IllnessRight Left Right Left

F 58 Asymptomatic Right deep white matter 3 4 None None

F 36 TIA Bilateral deep white matter 3 3 None None

F 49 TIA Bilateral frontal deep white matter

3 3 None None

F 33 TIA None 3 4 None None Hypertension

F 51 Asymptomatic None 3 4 None None

M 49 Asymptomatic None 3 3 None None

M 42 Asymptomatic None 1 4 None None



F 40 TIA Right frontal white matter 3 2 Moderate Moderate Hypertension

F 40 TIA Right frontal white matter 2 2 None None

F 25 TIA Bilateral deep white matter 3 3 Moderate Moderate Hyperlipidemia


F 47 TIA Bilateral deep white matter 4 4 None None

M 43 Asymptomatic None 3 3 Moderate Moderate

F 21 Asymptomatic Right parietal deep white matter

3 1 None None

F 49 Asymptomatic None 3 5 Severe Severe Diabetes mellitus

F 36 Asymptomatic None 3 2 Moderate None

M 44 TIA None 3 3 Severe Severe

F 39 Asymptomatic None 3 2 Severe Moderate

F 46 TIA Bilateral deep white matter 3 3 Moderate None Hypertension

M 23 TIA None 3 3 Severe Moderate

M 36 Asymptomatic Left frontal deep white matter

3 3 Moderate Moderate

Asymptomatic: Patients with neurological episodes such as syncope and transient ischemic attack (TIA) in childhood but remained asymptomatic after adolescence. Hemodynamic compromise was rated as severe when cerebrovascular reactivity (CVR) was <5% from the baseline, moderate when 5≤CVR<10%, and normal when 10%≤CVR. 10% (Appendix I in the online-only Data Supplement). WMH indicates white matter hyperintensities.


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superior frontal, right middle frontal, and left middle cingulate cortex of patients with higher Stroop test performance were

significantly higher than those of their counterparts. Similarly, these values of the tracts originating from the bilateral middle frontal, right anterior cingulate cortex, and left middle cingu-late cortex were significantly higher in patients with higher reading span test performance than their counterparts.

DiscussionAdult patients with MMD suffer long disease duration. Thus, adult MMD is useful for studying the subtle effects of chronic hypoperfusion on the brain microstructure. This study revealed a decrease in the bilateral PCC density and widespread white matter areas with an FA decrease and RD increase in patients with MMD, alterations that were associated with age. In addi-tion, the bilateral PCC density was significantly associated with hemodynamic compromise, and the mean FA values of the white matter tracts of the dorsolateral prefrontal, cingu-late, and inferior parietal regions were significantly associated with neuropsychological performance.

PCC is associated with arousal, attention, internally directed thoughts, and environmental change detection.15 Focal lesion confined to PCC has rarely been reported, there-fore, neurocognitive consequences have remained unclear. In stroke, memory disturbances rather than a perceptual error has been reported, however, concomitant involvement in the for-nix and the corpus callosum might have been responsible for the cognitive dysfunctions in a large part.16 Connectivity of PCC is reduced in aging, trauma, Alzheimer disease, autism, schizophrenia, depression, and attention deficit hyperactivity disorder.15,17,18 PCC comprises part of the default mode net-work and its failure to deactivate during the task is considered responsible for the attention lapses.19 In this study, we specu-late that the volume reduction in the cingulate may be because of the reduced white matter connectivity. Vulnerability of the posterior part of the cingulum may be explained by its high energetic demand, where PCC consumes 40% greater cerebral blood flow and glucose compared with other brain lesions.20

Figure 2. Results of whole brain voxel-based analy-sis of white matter using tract-based spatial sta-tistics showing alterations in the 4 major diffusion tensor imaging indices. Voxels with a significant fractional anisotropy (FA) decrease, radial diffusivity (RD) increase, and mean diffusivity (MD) increase are shown (threshold-free cluster enhancement-corrected P<0.05). Axial diffusivity (AD) alterations are shown without corrections for multiple compari-sons (uncorrected P<0.05).

Figure 1. Comparison of the gray matter density between the patients moyamoya disease (MMD) and controls. Decreased gray matter density is observed in the bilateral posterior cingulate cortex of patients with MMD and is highlighted in shades of blue (family-wise error-corrected: P<0.05). The color scale represents the P values.




We speculate that PCC is one of the key neural substrates of attention deficit frequently observed in adult MMD.

White matter is vulnerable to chronic ischemia.21 The reported white matter changes in chronic ischemia include demyelination, axonal loss, and gliosis.22–24 The observed altered DTI indices of white matter also reflect these changes. The major DTI indices are sensitive to changes in the brain’s microstructure associated with myelination, axonal membrane

integrity, axon and glial density, and coherence of axonal orien-tation.25 Generally, neuronal or axonal loss and myelin degen-eration are associated with MD increase, which is because of the loss of cell structures that restrict water molecular diffu-sion, and with FA decrease, which is because of a decline in the alignment degree of highly organized cellular structures (axons and myelin). The observation of a wider area of FA alterations than MD alterations suggests that FA is more sensitive to white

Figure 3. The scatterplots show the relationship between the mean values of each major diffusion tensor imaging index of the entire white matter skeleton and the gray matter density of the cingulate cortex. Significant positive and inverse correlations were observed between the mean fractional anisotropy (FA; r=0.54; P<0.0001) and radial diffusivity (RD; r=−0.41; P<0.01) and the gray matter density, respec-tively. AD indicates axial diffusivity; and MD, mean diffusivity.

Figure 4. The spatial distribution of areas revealing significant correlations between the mean fractional anisotropy (FA) of white matter tracts derived by probabilistic tractography and neuropsychologi-cal performance (uncorrected P<0.05). Results of probabilistic tractography of a patient are shown. Processing speed significantly correlated with the mean FA of the tracts originating from the left supe-rior frontal (SF) gyrus; Trail Making Test (TMT) A with the left middle frontal (MF) and bilateral supra-marginal gyrus; TMT B and A with the left posterior cingulate cortex; the Stroop test with the right SF, MF, and the left middle cingulate cortex (MCC); and the reading span test (RST) with the right SF, bilateral MF, right anterior cingulate cortex, and left MCC. The color scale represents the P values.




matter alterations. More specific information about myelin and axonal damage can be obtained by incorporating the direc-tional DTI metrics, such as RD and AD. The former reportedly reflects the degree of myelin breakdown, whereas the latter reflects axonal damage and Wallerian degeneration.26,27 The preferential increase in RD observed in this study may reflect that the major pathological change in white matter in MMD is from demyelination/myelin breakdown. In this study, the exploratory analysis revealed a trend toward AD decrease in the long white matter tracts that run posteroanteriorly, although none of these voxels survived after correction for multiple comparisons. The tendency toward AD decreases in these tracts may reflect axonal swelling associated with Wallerian degeneration. We hypothesize that these white matter tracts are more vulnerable to ischemia compared other tracts.

In this study, the altered white matter integrity did not sig-nificantly associate with hemodynamic compromise. Taken together, the observed correlations between the mean FA of the white matter skeleton and age suggest that the disease duration may have a higher effect on white matter integrity than the severity of ischemia.7,8 Alternatively, chronic isch-emia in MMD may lower the threshold for age-related decline in white matter integrity.21 Our results also showed an age-related decline in the PCC density, which suggests regional variation in vulnerability to chronic ischemia. The present results may provide some insight into the potential role of the revascularization surgery. It is conceivable that the already damaged gray and white matter may be less likely to normalize even after hemodynamic improvements. Given that the dura-tion of chronic ischemia rather than severity may have more effect on the white matter integrity, early surgical interven-tion might be effective for preventing microstructural damage and cognitive dysfunctions in adults. Similarly, early surgical intervention may facilitate normal white matter development and intellectual outcome in children.

Consistent with previous reports, impaired executive func-tion/attention and working memory were observed in ≈30% of patients with MMD.2,3,28 In this study, we investigated the role of the dorsolateral prefrontal cortex, inferior parietal lobe, and cingulate cortex because these areas are reportedly associated consistently with executive function and working memory/attention.29–31 The mean FA values of the dorsolateral prefron-tal area (middle and superior frontal gyri) significantly cor-related with neuropsychological performance, suggesting that the area serves as a domain for working memory, executive function, and attention. This observation is consistent with that of previous studies demonstrating the association between cognitive function and the integrity of white matter fiber tracts integrating the frontoparietal cortical areas.29 The frontopa-rietal control network constitutes the dorsolateral prefrontal cortex, anterior cingulate cortex, presupplementary motor area, anterior insula, and PCC.15 It should be emphasized that the mean FA values of the fibers originating from the left PCC were associated with TMT B and A in this study. TMT B and A is not associated with visuoperceptual and working memory and serves as a relatively pure indicator of executive control abilities.32 This observation indicates that the white matter connection from PCC is associated with executive function.

This study had some limitations. First, the study population was small. The lack of neuropsychological data for assessing the frontal lobe functions in the controls may have resulted in a lack of statistical significance across comparisons. Second, the seed regions putatively associated with frontal lobe-medi-ated cognitive functions were used for probabilistic tractogra-phy. However, previous functional MRI studies demonstrated that the temporal lobe is also associated with working mem-ory.33 Third, white matter integrity is associated with age and sex.34 Sex was not completely matched in the study popula-tion and may have influenced the results of the comparison between patients and controls. Further investigation in a large population, preferably a multicenter study, is warranted to help identify the prevalence of cognitive dysfunction and the relationship with other neuroimaging markers,35 which will ultimately lead to determine optimal indication for the revas-cularization surgery.

ConclusionsSteno-occlusive changes in the major cerebral arteries in MMD cause microstructural brain damage, primarily in the cerebral white matter and impair executive function, working memory, and attention. The clinical significance of this study findings is that early detection of microstructural changes can enable early therapeutic intervention to improve patient cogni-tive outcome.

Sources of FundingThis study was supported by a grant from the Research Committee on moyamoya disease, sponsored by the Ministry of Health, Labor, and Welfare of Japan.

DisclosuresNone.

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Naoki Nakayama and Kiyohiro HoukinKen Kazumata, Khin Khin Tha, Hisashi Narita, Ichiro Kusumi, Hideo Shichinohe, Masaki Ito,

Adult Moyamoya DiseaseChronic Ischemia Alters Brain Microstructural Integrity and Cognitive Performance in

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ONLINE SUPPLEMENT

Appendix-I: Hemodynamic status assessment

Cerebrovascular reactivity (CVR) was expressed as the percent changes of the regional cerebral blood flow (rCBF) from the baseline after

intravenous acetazolamide injection. CVR less than 15 % in the left or right middle cerebral artery territory was considered as hemodynamic compromise.

In 5 of 13 asymptomatic MMD patients, the hemodynamic status had already been evaluated by using positron emission computed tomography (PET) in

2004-2009. All of them had normal resting state rCBF, cerebral blood volume and oxygen extraction fraction. As none of them had ischemic episode, no

further hemodynamic assessment was carried out. These patients were rated as free of hemodynamic compromise based on the results of PET study.

Appendix-II: Neuropsychological assessment

The WAIS-III provides the index scores for overall intellectual ability (Full-scale IQ), language, verbal ability (Perception Reasoning/ Organization Index), auditory attention and mental manipulation (Working Memory/ Freedom from Distractibility Index), and visual-motor speed (Processing Speed Index) with the mean score of 100 and standard deviation of 20.

The WCST measures the ability for strategic planning, organized search, utilization of environmental feedback to shift cognitive sets, directing

behavior toward achieving a goal, and modulating impulsive responding1. It is known as a measure of executive function.

The Trail-Making Test - Part A and B assess the speed of information processing and executive functioning, respectively.

The CPT measures a person's sustained and selective attention and impulsivity. It is composed of repetitive, "boring" task that requires

concentration over a period of time.

The Stroop test measures sustained attention. A reaction time delay was examined in naming the color of the word printed in an unmatched color.

The RST is a complex verbal test which evaluates both storage and processing (i.e., reading) elements of working memory2. The scores are

expressed as the total number and proportion of words correctly recalled.

Appendix-III: The MR imaging scan parameters

The scan parameters for DTI were as follows: repetition time (TR)/echo time (TE)/flip angle = 5051 ms/85 ms/90◦, field of view = 224 x 224 mm2,

matrix size = 128 × 128, b-value = 1000 s mm-2, the number of diffusion gradient directions = 32, slice thickness = 3 mm, the number of slices = 43, and the

number of excitation =1. The 3D-MPRAGE was performed with TR/TE/flip angle = 6.8 ms/3.1ms/ 8 and inversion time (TI) = 1100 ms. The scan

parameters for T2-weighted imaging were TR/TE = 4137 ms/90 ms and effective echo train length = 15. Those for FLAIR imaging were TR/TE = 10000

ms/100 ms and TI = 2700 ms.

Appendix-IV: Comparison of grey matter density

The 3D-MPRAGE images were brain-extracted and grey matter-segmented before being registered to the MNI 152 standard space using

non-linear registration. The resulting images were then averaged and flipped along the x-axis to create a left-right symmetric, study-specific grey matter

template. Next, all native grey matter images were non-linearly registered to this study-specific template and modulated to correct for local expansion due

to the non-linear component of the spatial transformation. The modulated grey matter images were then smoothed with an isotropic Gaussian kernel with

sigma of 3mm. Finally, voxelwise general linear model was applied using a permutation-based non-parametric testing.

Appendix-V: TBSS

TBSS was used to align all subjects’ FA images to FMRIB58_FA standard-space image and affine the aligned images into 1x1x1 mm3 MNI152

standard space. An average FA image was created for each section. Then, the average FA images were used to create a mean FA skeleton by applying a

threshold of 0.2. Cross-subject statistics were performed for the voxels that form the skeleton. The nonlinear warps and skeleton projection were then applied

to the other DTI indices, i.e., radial diffusivity (RD), mean diffusivity (MD), and axial diffusivity (AD). TBSS of RD, MD, and AD was subsequently

performed.

Appendix-VI: Probabilistic tractography

The seed regions were generated by using automated anatomical atlas (AAL), and were transformed into the native T1-weighted images using

FLIRT algorithm. For fiber tracking, the probability distribution of diffusion directions in each voxel was estimated by using Bayesian sampling techniques

(BEDPOSTX). The voxels which had fewer streamlines than 15% of the maximum number of streamlines across all voxels in each reconstructed tract were

excluded. The reconstructed probability maps in each region were transformed to the binary images. Seed mask images were subtracted from the

binarized probability maps for creating white matter masks to measure the mean FA values of subcortical tissue.

Supplemental Table I. The neuropsychological performance of the MMD patients

Study

cut-off

The range (mean SD) of scores achieved by all

patients

Percent of patients with the scores lower than the cut-off value

The mean (SD) score achieved by the asymptomatic

patients

The mean (SD) score achieved by the

symptomatic patients

p

WAIS -III

verbal IQ 80

64-121 (95+13)

4.3% 98.9

(12.4) 92.1 (13.0) 0.2279

motor IQ 80

71-113 (93+11)

17.4% 95.6

(11.1) 90.3 (11.7) 0.2937

full scale IQ 80

65-120 (94+13)

8.7% 97.1

(12.4) 91.4 (12.9) 0.3145

subscore

verbal perception

61-111 (96+13)

26.1% 100.1 (10.0)

91.0 (15.0) 0.1112

perceptual

55-114 (95+13)

17.4% 99.6

(14.7) 89.2 (14.4) 0.1278

working memory

58-123 (93+14)

34.8% 95.3

(12.1) 89.7 (14.2) 0.3507

processing speed

63-133 (96+15)

30.4% 95.7

(10.7) 96.2 (18.2) 0.9389

TMT-A

87 35-113

(72.2 + 20.1) 13.0%

73.3 (18.7)

71.0 (22.6) 0.8048

TMT-B 100

58-217 (93.5+ 34.8)

26.0% 85.9

(16.2) 102.5 (48.3) 0.3131

B-A

60 -25-134

(21.2+33.2) 8.7%

12.7 (15.6)

31.5 (45.5) 0.212

WSCT CA 4

1-6 (4.9 + 1.4)

30.4% 4.8

(1.5) 5.0 (1.2) 0.212

PEM 2

0-6 (1.7 + 1.8)

34.7% 1.7

(1.5) 1.6 (2.4) 0.764

PEN 3

0-15 (2.6 + 3.7)

39.1% 2.6

(2.3) 4.0 (6.3) 1

Stroop

10 2-129

(14.3 + 26.7) 34.8% 7.8 (3.8) 22.9 (40.3) 0.11

CPT error 3

0-71 (6 + 14.8)

39.1% 2.5 (1.4) 10.9 (23.9) 0.1448

RT 480 ms

312.7 - 1533 (494 + 250.6)

34.8% 428.7 (95.2) 466.5 (100.8) 0.3878

RST

2 1.5-4

(2.5 + 0.6) 39.1% 2.3 (0.4) 2.8 (0.8) 0.0876

Supplemental Table II. The p-values (correlation coefficient) achieved in testing the correlation/ association between the mean FA values of each

cortical and subcortical-seed based probabilistic tract and Neuropsychological performance

verbal

IQ

motor

IQ f IQ VC PO WM PS

TMT

-A

TMT

-B B-A WSCT Stroop CPT RST

Frontal

Lt. SF 0.08

(0.39)

0.06

(0.40)

0.11

(0.36)

0.10

(0.37)

0.13

(0.34)

0.28

(0.25)

0.04

(0.45)

0.37

(0.20)

0.19

(0.29)

0.42

(0.18) 0.05 0.097 0.15 0.07

Rt. SF 0.93

(0.01)

0.92

(0.00)

0.81

(0.06)

0.82

(0.05)

0.50

(0.15)

0.48

(0.16)

0.10

(0.37)

0.79

(0.06)

0.83

(0.05)

0.70

(0.09) 0.66 0.002 0.89 0.18

Lt. MF 0.34

(0.22)

0.68

(0.07)

0.50

(0.14)

0.13

(0.34)

0.38

(0.20)

0.89

(0.03)

0.37

(0.21)

0.04

(0.43)

0.10

(0.36)

0.60

(0.12) 0.66 0.210 0.65 0.03

Rt. MF 0.34

(0.20)

0.43

(0.11)

0.48

(0.13)

0.22

(0.28)

0.25

(0.26)

0.72

(0.08)

0.13

(0.34)

0.36

(0.21)

0.41

(0.18)

0.77

(0.07) 0.33 0.004 0.81 0.02

Cingulum

Lt. ACC 0.09

(0.38)

0.14

(0.31)

0.06

(0.40)

0.33

(0.22)

0.42

(0.18)

0.05

(0.44)

0.16

(0.32)

0.28

(0.24)

0.89

(0.03)

0.42

(0.18) 0.55 0.139 0.88 0.08

Rt. ACC 0.39

(0.15)

0.52

(0.17)

0.45

(0.15)

0.28

(0.25)

0.13

(0.34)

0.21

(0.29)

0.64

(0.11)

0.12

(0.34)

0.35

(0.21)

0.96

(0.01) 0.44 0.744 0.84 0.048

Lt. DCC 0.97

(0.01)

0.89

(0.04)

0.94

(0.02)

0.69

(0.10)

0.38

(0.20)

0.81

(0.05)

0.87

(0.04)

0.26

(0.25)

0.93

(0.02)

0.57

(0.13) 0.67 0.016 0.90 0.04

Rt. DCC 0.93

(0.02)

0.88

(0.04)

0.97

(0.01)

0.99

(0.00)

0.21

(0.29)

0.72

(0.08)

0.69

(0.09)

0.37

(0.20)

0.70

(0.09)

0.34

(0.21) 0.59 0.491 0.91 0.22

Lt. PCC 0.52

(0.15)

0.27

(0.24)

0.43

(0.18)

0.65

(0.10)

0.31

(0.23)

0.28

(0.25)

0.63

(0.11)

0.05

(0.43)

0.47

(0.16)

0.048

(0.43) 0.91 0.957 0.17 0.98

Rt. PCC. 0.77

(0.07)

0.64

(0.10)

0.70

(0.09)

0.93

(0.02)

0.98

(0.01)

0.55

(0.14)

0.95

(0.01)

0.54

(0.14)

0.60

(0.12)

0.36

(0.21) 0.60 0.427 0.08 0.74

Parietal

Lt. SMG 0.94

(0.03)

0.83

(0.06)

1.00

(0.00)

0.62

(0.12)

0.83

(0.05)

0.74

(0.08)

0.39

(0.20)

0.03

(0.47)

0.73

(0.08)

0.37

(0.20) 0.60 0.668 0.19 0.13

Rt. SMG 0.49

(0.15)

0.67

(0.11)

0.65

(0.11)

0.21

(0.29)

0.51

(0.15)

0.99

(0.00)

0.56

(0.14)

0.03

(0.48)

0.44

(0.17)

0.64

(0.10) 0.81 0.917 0.07 0.0678

Lt. ANG 0.28

(0.25)

0.80

(0.06)

0.49

(0.16)

0.31

(0.23)

1.00

(0.00)

0.42

(0.18)

0.94

(0.02)

0.21

(0.28)

0.75

(0.07)

0.27

(0.24) 0.67 0.645 0.81 0.75

Rt. ANG 0.75

(0.05)

0.67

(0.11)

0.93

(0.02)

0.54

(0.14)

0.68

(0.10)

0.50

(0.16)

0.38

(0.20)

0.05

(0.42)

0.85

(0.04)

0.35

(0.21) 0.81 0.774 0.27 0.20

Lt. PCUN 0.43

(0.18)

0.88

(0.04)

0.52

(0.15)

0.47

(0.17)

0.57

(0.13)

0.11

(0.36)

0.83

(0.05)

0.66

(0.10)

0.88

(0.04)

0.92

(0.02) 0.88 0.322 0.08 0.87

Rt. PCUN 0.37

(0.21)

0.47

(0.16)

0.36

(0.21)

0.60

(0.12)

0.90

(0.03)

0.21

(0.29)

0.40

(0.19)

0.74

(0.08)

0.93

(0.02)

0.77

(0.07) 0.80 0.419 0.11 0.79

Thalamus

Lt. Thal 0.95

(0.02)

0.71

(0.07)

0.72

(0.08)

0.77

(0.07)

0.46

(0.17)

0.62

(0.12)

0.62

(0.11)

0.17

(0.30)

0.34

(0.22)

0.06

(0.41) 0.40 0.805 0.83 0.30

Rt. Thal 0.87

(0.04)

0.82

(0.05)

0.95

(0.01)

0.58

(0.13)

0.91

(0.03)

0.86

(0.04)

0.80

(0.06)

0.91

(0.03)

0.42

(0.18)

0.36

(0.21) 0.83 0.671 0.57 0.75

Abbreviations; IQ; Intelligent quotient score, VIQ; Vebal IQ, PIQ; Performance IQ, fIQ; full scale IQ, VC; verbal comprehension, PR; Perceptual reasoning, WM; working memory, PS; Processing speed, TMT; Trail-making test, WSCT; Wisconsin card sorting test, Stroop; Stroop test, CPT; Conceptual performance task, RST; Reading span test. Note: Uncorrected p<0.05 is bolded. The p-values which approach 0.05 are bolded and shown in italic.

Supplemental Figure I

Figure legends

Appendix-Figure I.

The scatterplots show correlation between the mean FA of the white matter skeleton and age. A significant inverse correlation was observed in the MMD

patients (r= -0.57, p< 0.005), but not in the control subjects (r= -0.19, p= 0.38).

References

1. Monchi O, Petrides M, Petre V, Worsley K, Dagher A. Wisconsin card sorting revisited: Distinct neural circuits participating in different stages of the task identified by event-related functional magnetic resonance imaging. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001;21:7733-7741

2. Hupet M, Desmette D, Schelstraete MA. What does daneman and carpenter's reading span really measure? Perceptual and motor skills. 1997;84:603-608

V

10 Stroke 日本語版 Vol. 10, No. 1

背景および目的：もやもや病（MMD）における前頭葉機能障害の根底にある機序は明らかでない。本研究では，成人MMD患者を対象に慢性虚血による微かな脳微細構造の変化の有無を検討し，その変化と神経心理学的検査データとの関連を評価した。方法：成人MMD患者 23 例および年齢の一致する対照 23例で 3D T1 強調画像および拡散テンソル画像を含むMRIを施行し，灰白質密度と主な拡散テンソル画像指標を各群で比較した。年齢，虚血症状，脳血行動態不全，神経心理学的検査データと患者に認められた変化の関連を検討した。結果： MMD患者の後帯状皮質で，脳血行動態不全（ p ＜

0.05）に伴う灰白質密度の低下が認められた。また，異方性比率の広範な低下と，一部領域の放射拡散係数および平均拡散係数の上昇が両側の白質に認められた。白質の異方性比率（ r ＝ 0.54， p ＜ 0.0001）および放射拡散係数（ r ＝－ 0.41， p ＜ 0.01）は，帯状皮質の灰白質密度と有意に関連した。外側前頭前野，帯状回，下頭頂小葉領域の白質神経路の平均異方性比率は，処理速度，実行機能／注意力，作動（業）記憶と有意に関連した。結論：成人MMDでは灰白質の変化より白質の異常が多くみられた。白質の損傷は認知機能障害の発症において中心的役割を果たしていると思われる。

成人もやもや病において脳微細構造の健全性および認知機能レベルは慢性虚血により変化する

Chronic Ischemia Alters Brain Microstructural Integrity and Cognitive Performance in Adult Moyamoya Disease

Ken Kazumata, MD 1 ; Khin Khin Tha, MD 2 ; Hisashi Narita, MD 3 ; Ichiro Kusumi, MD 3 ; Hideo Shichinohe, MD 1 ; Masaki Ito, MD 1 ; Naoki Nakayama, MD 1 ; Kiyohiro Houkin, MD 1 1 Departments of Neurosurgery; 2 Radiobiology and Medical Engineering; and 3 Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Stroke 2015; 46: 354-360. DOI: 10.1161/ STROKEAHA.114.007407.

もやもや病（MMD）は，脳主幹動脈の進行性閉塞を原因として脳基底部に発生した網状の側副血管を特徴とする 1 。主に外側前頭前野を介する実行機能／注意力および作動（業）記憶に支障が出ることから，外側前頭前野の虚血が神経認知機能障害の原因と考えられる 2,3 。最近の研究で神経認知機能障害と脳血流量低下の関連が明らかにされた 3 。しかし神経認知機能障害患者すべてに従来のMRI で脳梗塞の所見を認めるわけではない。つまり，MMDの神経認知機能障害の背景には従来のMRI の性能では検出できないような虚血による微かな微細構造の変化がある。従来のMRI では検出されない微かな灰白質の変化は，3次元（3D）MRI で灰白質密度をボクセルごとに比較することにより，軽度認知機能障害や統合失調症など多くの疾患で検出に成功している 4,5 。報告によれば，拡散テンソル画像（DTI）は白質の拡散特性の点で微細構造の変化に対する感度が高い 6-9 。著者らの知る限り，3D MRI で MMDの灰白質変化を評価した報告はない。MMDの白質の健全性をDTI で評価した報告はわずかながら存在する 6-8 。しかし，これらの報告では特定の関心

領域が使用され，評価した主なDTI 指標は異方性比率（FA）と平均拡散係数（MD）の 2つのみであった。白質のボクセル解析は，白質の健全性について詳細な局所的特徴を明らかにすることができ，トラクトグラフィーは解剖学的領域を走る主な白質神経路の健全性を視覚化することができる。さらに，軸方向拡散係数（AD）や放射拡散係数（RD）といった主要なDTI 指標を加えることによって，慢性虚血による白質損傷を特徴付けるために追加の情報を抽出することもできる。本研究では，灰白質および白質のボクセル解析とトラクトグラフィーで成人MMDのさまざまな脳領域の微細構造を調査し，このような微細構造変化と脳血行動態不全および神経認知機能障害の関係を評価した。

対象および方法

研究参加者本前向き研究は北海道大学病院の研究倫理委員会により承認された。書面の同意は全参加者から取得した。選択基準は，Willis 動脈輪閉塞症調査研究班の提唱す

KEYWORDS 　拡散，虚血，磁気共鳴画像法，もやもや病，白質疾患

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Stroke-J-v10-i1-Full2.indd 10Stroke-J-v10-i1-Full2.indd 10 16-Jun-15 10:27:1016-Jun-15 10:27:10

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成人もやもや病において脳微細構造の健全性および認知機能レベルは慢性虚血により変化する 11

るMMDの合意基準およびガイドラインに基づいて特発性MMDと臨床診断された 21歳以上の患者，とした 10 。除外基準は，ダウン症候群や神経線維腫症などを合併した疑似もやもや症候群（quasimoyamoya syndrome），従来のMRIで最大径 8 mmを超える皮質梗塞または皮質下病変，頭蓋内出血，本研究参加前の血行再建手術，脳卒中による明らかな神経脱落症状，認知機能に影響する併存症，とした。これらを除外後，23例（男性 6例，女性 17例，21～ 58歳。平均 40.9 ± 9.5 歳）が登録に至った。選択期間は 25カ月（2012 年 4月～ 2014 年 4月）であった。対照の選択基準は，精神または神経学的疾患の臨床的エビデンスがないこと，日本語版Nelson Adult Reading Test 11 による評価で知能指数が正常範囲であること，従来のMRI で脳病変が確認されないこと，認知機能に影響する薬剤を使用していないこと，とした。対照群の構成も 23 例（男性 10 例，女性 13 例，25 ～ 56 歳。平均39.0 ± 8.1 歳）であった。知能指数の推定平均値は 108.3 ± 6.6 であった。

血行動態の評価 MMD患者の血行動態は，SPECT（単一光子型コンピュータ断層撮影法）による脳血管反応性の評価で判断した。左または右中大脳動脈領域の脳血管反応性が15％未満の場合を脳血行動態不全とみなした。18 例にはMRI から 7日以内にSPECTを施行した（データ補遺資料 I）。

神経心理学的評価 MMD患者すべてに神経心理学的評価を実施した。前頭葉損傷による認知機能障害に感度が高い神経心理学的検査を使用し，ウェクスラー成人知能検査（WAIS）III，ウィスコンシンカードソーティング検査，トレイルメイキング検査（TMT，AおよびB），持続処理課題，ストループ検査，リーディングスパン検査を組み込んだ。詳細は別途記載した（データ補遺資料 II）。臨床データについて盲検化された神経心理士がこれらのテストを実施した。神経心理学的検査とMRIの間隔は 1カ月未満であった。

MRI 解析 MRI は 3.0 テスラの撮像装置（Achieva TX，Philips Medical Solutions, Best, The Netherlands）で実施した。3D MPRAGE（magnetization‒prepared rapid gradient-echo）法によるT1強調画像と軸位断シングルショット・スピンエコー・エコープラナー法によるDTI 画像の撮影により，微かな灰白質および白質の変化を評価した。撮像パラメータの詳細は別途記載した（データ補遺資

料 III）。さらに皮質および皮質下梗塞を除外して白質高信号域を評価するため，MMD患者で軸位断高速スピンエコー T2強調画像およびFLAIR（fluid-attenuated inversion recovery）画像を撮像した。

画像処理および評価灰白質変化の識別 3D MPRAGE画像でMMD患者と対照の灰白質密度をボクセルごとに比較した。FSL注）のボクセル形態計測ステップ（FSL-VBM，バージョン 4.1， http://www.fmrib.ox.ac.uk/fsl ）はデフォルトのパラメータを使用した 12,13

（データ補遺資料 IV）。年齢は共変量とした。Family-wise error注）補正後， p ＜ 0.05 を統計学的に有意と判定した。

白質変化の識別微かな白質の変化を見分けるため，FSLの Diffusion Toolbox およびデフォルトパラメータを使用したDTI から，4つの主要なDTI 指標（FA，MD，AD，RD）を最初に抽出した 12-14 。これらの指標を抽出する前に，渦電流の歪みおよび動きを補正した。次に，MMD患者と対照の主要なDTI 指標の差をFSLの一部である白質神経路の空間統計により検討した。ソフトウェア開発者の推奨するデフォルトのパラメータおよびステップを使用した（データ補遺資料V）。年齢を共変量とし，閾値のないクラスタ強化（threshold-free cluster enhancement）法で結果に多重比較の空間補正を行った。主要なDTI 指標それぞれについて，統計学的有意に達したボクセルの平均値と数（閾値のないクラスタ強化法で補正， p ＜0.05）を計算した。 FLIRTおよびBEDPOSTX（データ補遺資料VI）で確率的トラクトグラフィーを実施した。知能，作動記憶，実行機能／注意力に介在する 16 の皮質領域と両側の視床をシード領域として選択した。ターゲット領域には脳全体を選択した。各々の確率的神経路について，ボクセル数と平均FA値を計算した。

微細構造変化と脳血行動態不全および神経認知機能の相関 MMD患者で異常な灰白質密度を示すボクセルは，主要なDTI 白質指標との相関分析を行った。灰白質でも白質でも何らかの変化があれば，年齢，虚血症状の有無，脳血行動態不全，神経心理学的検査データとの相関につ

注：FSLはMRI/DTI 脳画像解析ソフトのライブラリー。注：ファミリーワイズ・エラー；多重検定で第一種エラーを起こす確率。


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いて分析した。上記の目的のため，Pearson の積率相関係数（年齢，WAIS-III，TMT A およびBとの相関）または 10,000 回を超える順列並べ替え検定（虚血症状の有無，脳血行動態不全，ウィスコンシンカードソーティング検査，ストループ検査，持続処理課題，リーディングスパン検査。後者 4つの課題にはカットオフ値を適用）を使用した。相関および比較はすべて p ＜ 0.05 で統計学的に有意と判定した。

結　果

患者の特徴患者の特徴を表に要約する。患者と対照の年齢（ p ＝0.47）および性別（ p ＝ 0.35）に有意差はなかった。症候性患者（一過性脳虚血発作 n＝ 10）と無症候性患者（n＝ 13）で，安静時脳血流量，脳血管反応性，併存危険因子の保有率に大きな差はなかった。T2強調画像およびFLAIR 画像で，MMD患者 10 例（43.5％）に白質高信号域が認められた。高信号域は症候性患者でも多かった（7/10， p ＜ 0.05）。MMD患者の総合知能指数は平均 94 ± 13 であった。患者の神経心理学的評価の結果をデータ補遺表 Iに要約する。症候性患者と無症候性患者において，総合知能指数，WAIS 検査のスコア，その他の神経心理学的検査の項目に大きな差はなかった。

灰白質の変化 FSL-VBMで両側後帯状皮質（PCC）の密度に有意な低下が認められた（図 1 ）。

白質の変化白質神経路の空間的統計では，MMD患者で広範囲にわたる有意なFAの低下とRDの上昇が認められた［それぞれ全構造の 55.2％および 42.5％，図 2 ］。FAおよびRDに変化があったボクセルも，有意なMDの上昇を示した。MDの上昇を示したボクセルは平均FA構造の20.9％を占めた。ADに関しては，多重比較の補正をしなかった場合，主に上縦束および帯状束で低下が認められたが（未補正 p ＜ 0.05），補正した場合そのようなボクセルは認められなかった。確率的トラクトグラフィーでも，MMD患者の白質神経路の一部で平均FAの低下が認められた。MMD患者の各神経路のボクセル数は対照群と大きく変わらなかった。

微細構造変化と脳血行動態不全および神経認知機能の相関患者の帯状皮質の密度は，白質構造の平均FA（ r ＝

0.54， p ＜ 0.0001）またはRD（ r ＝－ 0.41， p ＜ 0.01）と有意な相関を示した（図 3 ）。 MMD患者の両側後帯状皮質の密度（ http://fmri.wfubmc.edu/software/PickAtlas ）および白質構造の平均FAは，年齢と逆相関関係にあった（それぞれ r ＝－ 0.43， p ＜ 0.01 および r ＝－ 0.57， p ＜ 0.005，データ補遺図 I）。症候性患者と無症候性患者の間で局所灰白質密度および主要DTI 指標に著しい差はなかった。脳血行動態不全の患者は，対照に比べて後帯状皮質密度が有意に低かったが，白質構造の主要DTI 指標それぞれの平均値は 2群で差がなかった。後帯状皮質密度も白質構造の主要DTI 指標の平均値も，神経心理学的検査データと有意な関連はなかった。しかし，次の白質神経路の平均FA値は神経心理学的検査データと有意に関連した（データ補遺表 II，図 4 ）：左上前頭回由来の神経線維と処理速度（ r ＝ 0.45）；左中前頭回，左縁上回，右縁上回由来の神経線維とTMT A（それぞれ r ＝ 0.43，0.43，0.48）；左後帯状皮質由来の神経線維とTMT B およびA（ r ＝ 0.43）。ストループ検査の成績が高かった患者の右上前頭回，右中前頭回，左中帯状皮質に由来する神経路の平均FA値は，対照群より有意に高値であった。同様に，両側中前頭回，右前帯状皮質および左中帯状皮質に由来する神経路の平均FA値も，対照よりリーディングスパン検査の成績が高い患者で有意に高値であった。

考　察

成人MMD患者の罹患期間は長い。そのため脳の微細構造に対する慢性低灌流の微かな影響を研究するには，成人MMDは有用である。本研究はMMD患者の両側後帯状皮質密度の低下と，広範な白質領域におけるFAの低下およびRDの上昇を明らかにしたが，これらの変化は年齢と関連していた。さらに，両側後帯状皮質密度は脳血行動態不全と有意に関連し，背外側前頭前野，帯状回，下頭頂小葉領域の白質神経路の平均FA値は神経心理学的検査データと有意に関連した。後帯状皮質は覚醒，注意力，内向的思考，環境変化の発見に関連する 15 。後帯状皮質に限った局所的病変はほとんど報告されていないため，神経認知機能への影響はいまだ不明である。脳卒中では知覚的な誤りよりも記憶障害が報告されているが，脳弓および脳梁に併存する病変が認知機能障害の大きな原因と考えられる 16 。後帯状皮質の結合性は加齢，外傷，アルツハイマー病，自閉症，統合失調症，うつ病，注意欠陥多動障害で低下する 15,17,18 。後帯状皮質はデフォルトモードのネットワークの一部を構成するため，作業中にその活動を停止で


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表　患者の特徴

Suzuki 分類脳血行動態不全

性別年齢，歳臨床症状 WMHの場所右左右左併存症

女 58 無症候性右深部白質 3 4 なしなし

女 36 TIA 両側深部白質 3 3 なしなし

女 49 TIA 両側前頭深部白質 3 3 なしなし

女 33 TIA なし 3 4 なしなし高血圧

女 51 無症候性なし 3 4 なしなし

男 49 無症候性なし 3 3 なしなし

男 42 無症候性なし 1 4 なしなし



女 40 TIA 右前頭白質 3 2 中等度中等度高血圧

女 40 TIA 右前頭白質 2 2 なしなし

女 25 TIA 両側深部白質 3 3 中等度中等度高脂血症


女 47 TIA 両側深部白質 4 4 なしなし

男 43 無症候性なし 3 3 中等度中等度

女 21 無症候性右頭頂深部白質 3 1 なしなし

女 49 無症候性なし 3 5 重度重度糖尿病

女 36 無症候性なし 3 2 中等度なし

男 44 TIA なし 3 3 重度重度

女 39 無症候性なし 3 2 重度中等度

女 46 TIA 両側深部白質 3 3 中等度なし高血圧

男 23 TIA なし 3 3 重度中等度

男 36 無症候性左前頭深部白質 3 3 中等度中等度

無症候性：小児期に失神や一過性脳虚血発作（TIA）などの神経学的事象があったが，青年期以後は無症候のまま推移した患者。脳血行動態不全は脳血管反応性（CVR）が基準線から 5％未満の場合は重度，5％以上 10％未満の場合は中等度，10％以上の場合は正常と判断した。10％（データ補遺資料 I）。WMH：白質高信号域。

きないことが注意力喪失の原因であると考えられている 19 。本研究において，帯状回の容積減少は白質の結合性の減少によるものと推測される。帯状回後部の脆弱性は，その高いエネルギー需要によって説明できるかもしれない。他の脳部位と比べて後帯状皮質で消費される脳血流と糖は 40％以上も多い 20 。後帯状皮質は成人MMDでよくみられる注意力欠陥の重要な神経要素の 1つであると思われる。

白質は慢性虚血に弱い 21 。慢性虚血で報告されている白質の変化には，脱髄，軸索消失，神経膠症などがある 22-24 。今回観察された白質のDTI 指標の変化もこれらの変化を表す。主要なDTI 指標は，髄鞘形成，軸索膜の健全性，軸索と膠細胞の密度，軸索方向の一貫性と関連した脳の微細構造の変化に敏感である 25 。一般的に，神経細胞または軸索の消失，髄鞘の変性はMDの上昇に関連があるが，これは水分子の拡散を制限する細胞構造が消失するためである。また，FAの低下にも関連があり，これは高度に組織化された細胞構造（軸索および髄鞘）の整列度の低下によるものである。MDの変化よりFAの変化領域が大きかったことは，FAがより白質の変化に対して敏感であることを示す。髄鞘および軸索の損傷

に関する詳細な情報は，RDおよびADなど方向に関連したDTI 指標を取り入れることで得られる。前者は髄鞘破損度を反映し，後者は軸索損傷とワーラー変性を反映するとされている 26,27 。本研究で認められたRDの優先的な上昇は，MMDにおける白質の主な病理的変化が脱髄／髄鞘破損に起因することを表している可能性がある。本研究の探索的解析の結果，後ろから前に走る長い白質神経路でADが低下する傾向が認められたが，多重比較の補正後にそのようなボクセルは残らなかった。これらの神経路で低下傾向にあったADは，ワーラー変性に伴う軸索腫脹を表す可能性がある。これらの白質神経路は，他の神経路よりも虚血に弱いと想定される。

本研究において，白質健全性の変化と，脳血行動態不全に有意な関連はなかった。総合的にみて，白質構造の平均FA値と年齢に認められた相関は，虚血の重症度より罹患期間が白質の健全性に大きく影響することを示唆する 7,8 。あるいはMMDの慢性虚血により，加齢に伴う白質健全性の減少閾値が下がるかもしれない 21 。本研究結果でも加齢に伴う後帯状皮質密度の低下が認められたが，これは慢性虚血に対する脆弱性の局所的差異を示


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図 1

もやもや病（MMD）患者と対照の灰白質密度の比較。MMD患者の両側後帯状皮質で低下した灰白質密度を青で強調表示した（family-wise error補正， p ＜0.05）。カラースケールは p 値を表す。

P A R L

R LR L

R

0.05 0.0001

L R L

R

FA

RD

AD

MD

L 正常有意な変化

図 2

白質神経路の空間的統計による脳全体の白質ボクセル解析の結果，4つの主要な拡散テンソル画像指標に変化がみられた。著しい異方性比率（FA）の低下，放射拡散係数（RD）の上昇，平均拡散係数（MD）の上昇を示すボクセルを表示する（閾値のないクラスタ強化法補正， p ＜ 0.05）。軸方向拡散係数（AD）の変化は，多重比較の補正をせずに表示してある（未補正 p ＜ 0.05）。

唆する。これらの結果は，血行再建手術の潜在的役割について一定の方向性を示しているかもしれない。すでに損傷を受けた灰白質および白質は，血行動態が改善しても正常化する可能性は低いと考えられる。慢性虚血の持

続期間が重症度より白質の健全性に影響するならば，微細構造の損傷および成人の認知機能障害の予防には早期の外科的介入が効果的かもしれない。同じく小児でも，早期の外科的介入は正常な白質の発達と知能的な成長を促す可能性がある。過去の報告と一致して，実行機能／注意力および作動記憶の障害はMMD患者の約 30％で認められた 2,3,28 。本研究では背外側前頭前野皮質，下頭頂小葉，帯状皮質の役割を調査したが，これらの領域は常に実行機能／作動記憶／注意力と関係すると報告されている 29-31 。背外側前頭前野（中前頭回および上前頭回）の平均FA値と神経心理学的検査データの有意な相関は，ここが作動記憶，実行機能，注意力を担当する領域であることを示唆する。この観察結果は，認知機能と前頭頭頂皮質領域を統合する白質神経路の健全性の関連を明らかにした過去の研究と一致する 29 。前頭頭頂領域の制御ネットワークは背外側前頭前野皮質，前帯状皮質，前補足運動野，前島皮質，後帯状皮質から構成される 15 。本研究において，左後帯状皮質に由来する神経線維の平均FA値がTMT B およびAと関連していたことは注目すべき結果である。TMT B およびAは視知覚記憶および作動記憶には関係なく，比較的純粋な実行制御能力の指標として役立つ 32 。今回の観察結果は後帯状皮質からの白質結合が実行機能に関与していることを示す。本研究には一定の限界がある。第一に，研究対象集団が少なかった。対照群の前頭葉機能評価のための神経心理学的データの欠如は，各々の比較で統計学的有意差の不足につながった可能性がある。第二に，前頭葉が介在する認知機能に関連すると推測されたシード領域を確率的トラクトグラフィーに使用した。しかし，過去の機能


V


図 3 全白質構造の主要な拡散テンソル画像指標の平均値と帯状皮質の灰白質密度の関係を表した散布図。平均異方性比率（FA， r ＝ 0.54， p ＜0.0001）および放射拡散係数（RD， r ＝－ 0.41， p ＜0.01）と灰白質密度の間にそれぞれ有意な正および逆の相関が認められた。AD：軸方向拡散係数，MD：平均拡散係数。

0.00055

0.4 0.45 0.55帯状皮質の灰白質密度

帯状皮質の灰白質密度帯状皮質の灰白質密度

帯状皮質の灰白質密度

FA

0.65 0.750.5 0.6

r = 0.54p < 0.0001

r = ‒ 0.41p < 0.01

r = 0.10p = 0.50

r = ‒ 0.26p = 0.07

0.7 0.8 0.4 0.45 0.55 0.65 0.750.5 0.6 0.7 0.8

0.4 0.45 0.55 0.65 0.750.5 0.6 0.7 0.80.4 0.45 0.55 0.65 0.750.5 0.6 0.7 0.8

RD ( mm

2/S

)AD ( mm

2/S

)

MD ( mm

2/S

)0.50.490.480.470.460.450.440.430.420.41

0.00054

0.00053

0.00052

0.00051

0.00049

0.00048

0.00047

0.0005

0.00083

0.00082

0.00081

0.0008

0.00079

0.00077

0.00076

0.00075

0.00074

0.0078

0.00041

0.0004

0.00039

0.0038

0.00037

0.00035

0.00034

0.00033

0.0036

図 4

確率的トラクトグラフィーにより導き出した白質神経路の平均異方性比率（FA）と神経心理学的検査データの有意な相関を示す領域の空間分布（未補正 p ＜ 0.05）。一人の患者の確率的トラクトグラフィーの結果を表示した。処理速度は左上前頭回（SF）に由来する神経路の平均 FAと有意に相関した。同じく，トレイルメイキング検査（TMT）Aは左中前頭回（MF）および両側縁上回と，TMT B およびAは左後帯状皮質と，ストループ検査は右SF，MF，左中帯状皮質（MCC）と，リーディングスパン検査（RST）は右SF，両側MF，右前帯状皮質，左MCCと有意に相関した。カラースケールは p 値を表す。

0.001

R L R L R L R L

R LR LR LR LR

処理速度 TMT-A TMT-B-A ストループ RST

L

P A

0.05

的MRIの研究で側頭葉も作動記憶と関連することが明らかになっている 33 。第三に，白質の健全性は年齢および性別に関連する 34 。対象集団の性別が完全に一致していなかったため，患者群と対照群の比較結果に影響したかもしれない。認知機能障害の有病率および他の神経画像マーカーとの関係を特定するには，大規模集団での，できれば多施設共同研究による調査研究がさらに必要であ

る 35 。最終的には，これが血行再建手術の最適な適応症の決定に役立つであろう。

結　論

MMDにおいて，脳主幹動脈の狭窄閉塞性変化は主に脳白質の微細構造に損傷を与え，実行機能，作動記憶，


V


注意力を低下させる。本研究の臨床的意義は，微細構造の変化を早期発見すれば早期の治療介入により認知機能の転帰を改善させ得る可能性である。

研究費財源本研究は厚生労働省の支援するもやもや病研究班から補助金を受領した。

情報開示なし。

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