Chronic Ischemia Alters Brain Microstructural Integrity

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
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
M
oyamoya disease (MMD) is characterized by the presence 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, primarily 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 neurocognitive dysfunction had cerebral infarction on conventional 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-byvoxel 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 knowledge, no reports have evaluated gray matter changes in MMD
using 3D MRI. There are only few reports on DTI assessments of MMD white matter integrity.6–8 Nevertheless, these
reports used a specified region-of-interest approach and evaluated only 2 major DTI indices, such as fractional anisotropy
(FA) and mean diffusivity (MD). Voxel-based analysis of
white matter can provide detailed topographical characteristics 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 characterizing 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 different regions in adult MMD by a voxel-based analysis of gray
and white matter and tractography, and evaluated the relationship of these microstructural alterations with hemodynamic
compromise and neurocognitive dysfunction.
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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by guest on May 11, 2016
354
Kazumata et al Brain Microstructural Changes in Moyamoya Disease 355
Materials and Methods
Participants
This prospective study was approved by the Research Ethics
Committee of Hokkaido University Hospital. Written informed consent was obtained from all participants.
The inclusion criteria were clinical diagnosis of idiopathic MMD
according to the consensus criteria and guideline for MMD proposed by the Research Committee on Spontaneous Occlusion of the
Circle of Willis and age of >20.10 The exclusion criteria were quasimoyamoya 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 hemorrhage, revascularization surgery before the study, apparent neurological 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 subjects (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 Assessment
Cerebrovascular reactivity assessed by single positron emission computed tomography was used to determine the hemodynamic status in
patients with MMD. A cerebrovascular reactivity of <15% in the leftor right-middle cerebral artery territory was considered as a hemodynamic 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 Assessment
The 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 neuropsychological tests and MRI was <1 month.
MRI Analysis
MRI was performed on a 3.0-T imager (Achieva TX; Philips Medical
Solutions, Best, The Netherlands). Three-dimensional magnetization–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 detailed elsewhere (Appendix III in the online-only Data Supplement).
In addition, axial fast spin-echo T2-weighted imaging and fluid-attenuated inversion recovery imaging were also performed in patients
with MMD to rule out cortical and subcortical infarctions and evaluate white matter hyperintensities.
Image Processing and Evaluation
Identification of Gray Matter Alterations
Three-dimensional magnetization–prepared rapid gradient-echo images were used to compare gray matter density voxel-by-voxel between 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 considered statistically significant.
Identification of White Matter Alterations
To 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 extracting 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 threshold-free cluster enhancement. For each major DTI index, the mean
value and number of voxels reaching statistical significance (threshold-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 intelligence, 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 Function
Voxels 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 correlation analysis (correlation with age, Wechsler Adult Intelligent scaleIII, 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.
Results
Patient Characteristics
Patient 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, cerebrovascular reactivity, and prevalence of comorbid risk factors
did not vary significantly between the symptomatic (ie, transient 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 inversion 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 summarized 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 Alterations
FSL-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
Table. Patient Characteristics
Suzuki Grade
Hemodynamic Compromise
Age, y
Clinical
Presentation
Location of WMH
Right
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
Sex
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
53
Asymptomatic
None
4
2
None
None
F
34
Asymptomatic
None
3
3
None
None
F
40
TIA
Right frontal white matter
3
2
Moderate
Moderate
F
40
TIA
Right frontal white matter
2
2
None
None
F
25
TIA
Bilateral deep white matter
3
3
Moderate
Moderate
F
46
Asymptomatic
None
4
4
None
None
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
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
M
23
TIA
None
3
3
Severe
Moderate
M
36
Asymptomatic
Left frontal deep white
matter
3
3
Moderate
Moderate
Comorbid Illness
Hypertension
Hypertension
Hyperlipidemia
Diabetes mellitus
Hypertension
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.
White Matter Alterations
Tract-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 significant MD increases. Voxels showing MD increases occupied
20.9% of the mean FA skeleton. Regarding AD, no voxels survived after correction for multiple comparisons, although AD
decreases were observed mainly at the superior longitudinal
fasciculus and cingulate bundle when correction was not performed (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
Function
The density of the cingulate cortex of the patients significantly 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 skeleton 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 matter 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 originating 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
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Kazumata et al Brain Microstructural Changes in Moyamoya Disease 357
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 cingulate cortex were significantly higher in patients with higher
reading span test performance than their counterparts.
Discussion
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.
superior frontal, right middle frontal, and left middle cingulate
cortex of patients with higher Stroop test performance were
Adult 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 addition, the bilateral PCC density was significantly associated
with hemodynamic compromise, and the mean FA values of
the white matter tracts of the dorsolateral prefrontal, cingulate, 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, therefore, neurocognitive consequences have remained unclear. In
stroke, memory disturbances rather than a perceptual error has
been reported, however, concomitant involvement in the fornix 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 network and its failure to deactivate during the task is considered
responsible for the attention lapses.19 In this study, we speculate 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 analysis of white matter using tract-based spatial statistics 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 enhancementcorrected P<0.05). Axial diffusivity (AD) alterations
are shown without corrections for multiple comparisons (uncorrected P<0.05).
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358 Stroke February 2015
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, respectively. AD indicates axial diffusivity; and MD, mean diffusivity.
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 orientation.25 Generally, neuronal or axonal loss and myelin degeneration are associated with MD increase, which is because of
the loss of cell structures that restrict water molecular diffusion, 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 4. The spatial distribution of areas revealing
significant correlations between the mean fractional
anisotropy (FA) of white matter tracts derived by
probabilistic tractography and neuropsychological 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 superior frontal (SF) gyrus; Trail Making Test (TMT) A
with the left middle frontal (MF) and bilateral supramarginal 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.
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Kazumata et al Brain Microstructural Changes in Moyamoya Disease 359
matter alterations. More specific information about myelin and
axonal damage can be obtained by incorporating the directional 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 significantly 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 ischemia in MMD may lower the threshold for age-related decline
in white matter integrity.21 Our results also showed an agerelated 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 duration of chronic ischemia rather than severity may have more
effect on the white matter integrity, early surgical intervention 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 function/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 prefrontal area (middle and superior frontal gyri) significantly correlated 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 frontoparietal 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-mediated cognitive functions were used for probabilistic tractography. However, previous functional MRI studies demonstrated
that the temporal lobe is also associated with working memory.33 Third, white matter integrity is associated with age and
sex.34 Sex was not completely matched in the study population 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 revascularization surgery.
Conclusions
Steno-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 cognitive outcome.
Sources of Funding
This study was supported by a grant from the Research Committee
on moyamoya disease, sponsored by the Ministry of Health, Labor,
and Welfare of Japan.
Disclosures
None.
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Chronic Ischemia Alters Brain Microstructural Integrity and Cognitive Performance in
Adult Moyamoya Disease
Ken Kazumata, Khin Khin Tha, Hisashi Narita, Ichiro Kusumi, Hideo Shichinohe, Masaki Ito,
Naoki Nakayama and Kiyohiro Houkin
Stroke. 2015;46:354-360; originally published online December 23, 2014;
doi: 10.1161/STROKEAHA.114.007407
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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
The mean (SD) score
achieved by the
achieved by the
asymptomatic
symptomatic
patients
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
91.0 (15.0)
0.1112
89.2 (14.4)
0.1278
subscore
verbal
61-111
perception
(96+13)
55-114
perceptual
(95+13)
26.1%
17.4%
100.1
(10.0)
99.6
(14.7)
working
58-123
memory
processing
(93+14)
63-133
speed
(96+15)
TMT-A
87
TMT-B
100
B-A
60
WSCT
CA
4
PEM
2
PEN
3
10
Stroop
CPT
error
3
35-113
(72.2 + 20.1)
58-217
(93.5+ 34.8)
-25-134
(21.2+33.2)
1-6
(4.9 + 1.4)
0-6
(1.7 + 1.8)
0-15
(2.6 + 3.7)
2-129
(14.3 + 26.7)
0-71
(6 + 14.8)
34.8%
30.4%
13.0%
26.0%
8.7%
30.4%
34.7%
39.1%
95.3
(12.1)
95.7
(10.7)
73.3
(18.7)
85.9
(16.2)
12.7
(15.6)
4.8
(1.5)
1.7
(1.5)
2.6
(2.3)
89.7 (14.2)
0.3507
96.2 (18.2)
0.9389
71.0 (22.6)
0.8048
102.5 (48.3)
0.3131
31.5 (45.5)
0.212
5.0 (1.2)
0.212
1.6 (2.4)
0.764
4.0 (6.3)
1
34.8%
7.8 (3.8)
22.9 (40.3)
0.11
39.1%
2.5 (1.4)
10.9 (23.9)
0.1448
RT
RST
480 ms
2
312.7 - 1533
(494 + 250.6)
1.5-4
(2.5 + 0.6)
34.8%
428.7 (95.2)
466.5 (100.8)
0.3878
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
motor
f IQ
VC
PO
WM
PS
TMT
TMT
-A
-B
B-A
IQ
IQ
0.08
0.06
0.11
0.10
0.13
0.28
0.04
0.37
0.19
0.42
(0.39)
(0.40)
(0.36)
(0.37)
(0.34)
(0.25)
(0.45)
(0.20)
(0.29)
(0.18)
0.93
0.92
0.81
0.82
0.50
0.48
0.10
0.79
0.83
0.70
(0.01)
(0.00)
(0.06)
(0.05)
(0.15)
(0.16)
(0.37)
(0.06)
(0.05)
(0.09)
0.34
0.68
0.50
0.13
0.38
0.89
0.37
0.04
0.10
0.60
(0.22)
(0.07)
(0.14)
(0.34)
(0.20)
(0.03)
(0.21)
(0.43)
(0.36)
(0.12)
0.34
0.43
0.48
0.22
0.25
0.72
0.13
0.36
0.41
0.77
(0.20)
(0.11)
(0.13)
(0.28)
(0.26)
(0.08)
(0.34)
(0.21)
(0.18)
(0.07)
0.09
0.14
0.06
0.33
0.42
0.05
0.16
0.28
0.89
0.42
(0.38)
(0.31)
(0.40)
(0.22)
(0.18)
(0.44)
(0.32)
(0.24)
(0.03)
(0.18)
0.39
0.52
0.45
0.28
0.13
0.21
0.64
0.12
0.35
0.96
(0.15)
(0.17)
(0.15)
(0.25)
(0.34)
(0.29)
(0.11)
(0.34)
(0.21)
(0.01)
0.97
0.89
0.94
0.69
0.38
0.81
0.87
0.26
0.93
0.57
(0.01)
(0.04)
(0.02)
(0.10)
(0.20)
(0.05)
(0.04)
(0.25)
(0.02)
(0.13)
0.93
0.88
0.97
0.99
0.21
0.72
0.69
0.37
0.70
0.34
(0.02)
(0.04)
(0.01)
(0.00)
(0.29)
(0.08)
(0.09)
(0.20)
(0.09)
(0.21)
WSCT
Stroop
CPT
RST
0.05
0.097
0.15
0.07
0.66
0.002
0.89
0.18
0.66
0.210
0.65
0.03
0.33
0.004
0.81
0.02
0.55
0.139
0.88
0.08
0.44
0.744
0.84
0.048
0.67
0.016
0.90
0.04
0.59
0.491
0.91
0.22
Frontal
Lt. SF
Rt. SF
Lt. MF
Rt. MF
Cingulum
Lt. ACC
Rt. ACC
Lt. DCC
Rt. DCC
Lt. PCC
Rt. PCC.
0.52
0.27
0.43
0.65
0.31
0.28
0.63
0.05
0.47
0.048
(0.15)
(0.24)
(0.18)
(0.10)
(0.23)
(0.25)
(0.11)
(0.43)
(0.16)
(0.43)
0.77
0.64
0.70
0.93
0.98
0.55
0.95
0.54
0.60
0.36
(0.07)
(0.10)
(0.09)
(0.02)
(0.01)
(0.14)
(0.01)
(0.14)
(0.12)
(0.21)
0.94
0.83
1.00
0.62
0.83
0.74
0.39
0.03
0.73
0.37
(0.03)
(0.06)
(0.00)
(0.12)
(0.05)
(0.08)
(0.20)
(0.47)
(0.08)
(0.20)
0.49
0.67
0.65
0.21
0.51
0.99
0.56
0.03
0.44
0.64
(0.15)
(0.11)
(0.11)
(0.29)
(0.15)
(0.00)
(0.14)
(0.48)
(0.17)
(0.10)
0.28
0.80
0.49
0.31
1.00
0.42
0.94
0.21
0.75
0.27
(0.25)
(0.06)
(0.16)
(0.23)
(0.00)
(0.18)
(0.02)
(0.28)
(0.07)
(0.24)
0.75
0.67
0.93
0.54
0.68
0.50
0.38
0.05
0.85
0.35
(0.05)
(0.11)
(0.02)
(0.14)
(0.10)
(0.16)
(0.20)
(0.42)
(0.04)
(0.21)
0.43
0.88
0.52
0.47
0.57
0.11
0.83
0.66
0.88
0.92
(0.18)
(0.04)
(0.15)
(0.17)
(0.13)
(0.36)
(0.05)
(0.10)
(0.04)
(0.02)
0.37
0.47
0.36
0.60
0.90
0.21
0.40
0.74
0.93
0.77
(0.21)
(0.16)
(0.21)
(0.12)
(0.03)
(0.29)
(0.19)
(0.08)
(0.02)
(0.07)
0.95
0.71
0.72
0.77
0.46
0.62
0.62
0.17
0.34
0.06
(0.02)
(0.07)
(0.08)
(0.07)
(0.17)
(0.12)
(0.11)
(0.30)
(0.22)
(0.41)
0.87
0.82
0.95
0.58
0.91
0.86
0.80
0.91
0.42
0.36
(0.04)
(0.05)
(0.01)
(0.13)
(0.03)
(0.04)
(0.06)
(0.03)
(0.18)
(0.21)
0.91
0.957
0.17
0.98
0.60
0.427
0.08
0.74
0.60
0.668
0.19
0.13
0.81
0.917
0.07
0.0678
0.67
0.645
0.81
0.75
0.81
0.774
0.27
0.20
0.88
0.322
0.08
0.87
0.80
0.419
0.11
0.79
0.40
0.805
0.83
0.30
0.83
0.671
0.57
0.75
Parietal
Lt. SMG
Rt. SMG
Lt. ANG
Rt. ANG
Lt. PCUN
Rt. PCUN
Thalamus
Lt. Thal
Rt. Thal
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
10
Stroke 日本語版 Vol. 10, No. 1
Full Article
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, MD1; Khin Khin Tha, MD2; Hisashi Narita, MD3; Ichiro Kusumi, MD3;
Hideo Shichinohe, MD1; Masaki Ito, MD1; Naoki Nakayama, MD1; Kiyohiro Houkin, MD1
1
Departments of Neurosurgery; 2Radiobiology and Medical Engineering; and 3Psychiatry, Hokkaido University Graduate School of
Medicine, Sapporo, Japan
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。
Stroke 2015; 46: 354-360. DOI: 10.1161/ STROKEAHA.114.007407.
KEYWORDS 拡散，虚血，磁気共鳴画像法，もやもや病，白質疾患
もやもや病（ MMD ）は，脳主幹動脈の進行性閉塞を原
領域が使用され，評価した主な DTI 指標は異方性比率
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
（ FA ）と平均拡散係数（ MD ）の 2 つのみであった。白質
る 1。主に外側前頭前野を介する実行機能／注意力およ
のボクセル解析は，白質の健全性について詳細な局所的
び作動（業）記憶に支障が出ることから，外側前頭前野
特徴を明らかにすることができ，トラクトグラフィーは
2,3
。最近
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
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
ることができる。さらに，軸方向拡散係数（ AD ）や放射
かにされた 3。しかし神経認知機能障害患者すべてに従
拡散係数（ RD ）といった主要な DTI 指標を加えること
来の MRI で脳梗塞の所見を認めるわけではない。つま
によって，慢性虚血による白質損傷を特徴付けるために
り，MMD の神経認知機能障害の背景には従来の MRI の
追加の情報を抽出することもできる。
の虚血が神経認知機能障害の原因と考えられる
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。
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
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
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。
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
対象および方法
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
V
がら存在する
Stroke-J-v10-i1-Full2.indd 10
6-8
。しかし，これらの報告では特定の関心
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
16-Jun-15 10:27:10
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
る MMD の合意基準およびガイドラインに基づいて特発
11
料 III ）
。さらに皮質および皮質下梗塞を除外して白質
性 MMD と臨床診断された 21 歳以上の患者，とした。
高信号域を評価するため，MMD 患者で軸位断高速スピ
除外基準は，ダウン症候群や神経線維腫症などを合併し
ンエコー T2 強調画像および FLAIR（ fluid-attenuated
た疑似もやもや症候群（quasimoyamoya syndrome）
，従来
inversion recovery ）画像を撮像した。
10
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
画像処理および評価
による明らかな神経脱落症状，認知機能に影響する併存
灰白質変化の識別
症，とした。これらを除外後，23 例（男性 6 例，女性 17
3D MPRAGE 画像で MMD 患者と対照の灰白質密度を
例，21 ∼ 58 歳。平均 40.9 ± 9.5 歳）が登録に至った。選
ボクセルごとに比較した。FSL 注）のボクセル形態計測ス
択期間は 25 カ月（2012 年 4 月∼ 2014 年 4 月）であった。
テップ（ FSL-VBM，バージョン 4.1，http://www.fmrib.
対照の選択基準は，精神または神経学的疾患の臨床的
ox.ac.uk/fsl ）はデフォルトのパラメータを使用した 12,13
エビデンスがないこと，日本語版 Nelson Adult Reading
（データ補遺資料 IV ）
。年齢は共変量とした。Family-
Test による評価で知能指数が正常範囲であること，従
wise error 注）補正後，p ＜ 0.05 を統計学的に有意と判定
来の MRI で脳病変が確認されないこと，認知機能に影
した。
11
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。
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
血行動態の評価
初に抽出した 12-14。これらの指標を抽出する前に，渦電
MMD 患者の血行動態は，SPECT（単一光子型コン
流の歪みおよび動きを補正した。次に，MMD 患者と対
ピュータ断層撮影法）による脳血管反応性の評価で判
照の主要な DTI 指標の差を FSL の一部である白質神経
断した。左または右中大脳動脈領域の脳血管反応性が
路の空間統計により検討した。ソフトウェア開発者の推
15％未満の場合を脳血行動態不全とみなした。18 例に
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
は MRI から 7 日以内に SPECT を施行した（データ補
た（データ補遺資料 V ）
。年齢を共変量とし，閾値のな
遺資料 I ）。
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
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
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。
査を使用し，
ウェクスラー成人知能検査（WAIS）III，
ウィ
FLIRT および BEDPOSTX（データ補遺資料 VI ）で
スコンシンカードソーティング検査，トレイルメイキン
確率的トラクトグラフィーを実施した。知能，作動記憶，
グ検査（TMT，A および B）
，持続処理課題，ストループ
実行機能／注意力に介在する 16 の皮質領域と両側の視
検査，リーディングスパン検査を組み込んだ。詳細は別
床をシード領域として選択した。ターゲット領域には脳
途記載した（データ補遺資料 II ）
。臨床データについて盲
全体を選択した。各々の確率的神経路について，ボクセ
検化された神経心理士がこれらのテストを実施した。神
ル数と平均 FA 値を計算した。
経心理学的検査と MRI の間隔は 1 カ月未満であった。
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
MRI 解析
MRI は 3.0 テスラの撮像装置（ Achieva TX，Philips
関
MMD 患者で異常な灰白質密度を示すボクセルは，主
Medical Solutions, Best, The Netherlands ）で実施した。
要な DTI 白質指標との相関分析を行った。灰白質でも
3D MPRAGE（ magnetization‒prepared rapid gradient-
白質でも何らかの変化があれば，年齢，虚血症状の有無，
echo ）法による T1 強調画像と軸位断シングルショット・
脳血行動態不全，神経心理学的検査データとの相関につ
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
Stroke-J-v10-i1-Full2.indd 11
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。
16-Jun-15 10:27:11
V
12
Stroke 日本語版 Vol. 10, No. 1
いて分析した。上記の目的のため，Pearson の積率相関
0.54，p ＜ 0.0001 ）または RD（ r ＝ − 0.41，p ＜ 0.01 ）
係数（年齢，WAIS-III，TMT A および B との相関）ま
と有意な相関を示した（図 3 ）
。
たは 10,000 回を超える順列並べ替え検定（虚血症状の有
MMD 患者の両側後帯状皮質の密度（ http://fmri.
無，脳血行動態不全，ウィスコンシンカードソーティン
wfubmc.edu/software/PickAtlas ）および白質構造の平均
グ検査，ストループ検査，持続処理課題，リーディング
FA は，
年齢と逆相関関係にあった（それぞれ r ＝− 0.43，
スパン検査。後者 4 つの課題にはカットオフ値を適用）
p ＜ 0.01 および r ＝− 0.57，
p ＜ 0.005，データ補遺図 I）
。
を使用した。相関および比較はすべて p ＜ 0.05 で統計
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
学的に有意と判定した。
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
結果
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。
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 ＝
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。
0.47 ）および性別（ p ＝ 0.35 ）に有意差はなかった。症
しかし，次の白質神経路の平均 FA 値は神経心理学的検
候性患者（一過性脳虚血発作 n ＝ 10 ）と無症候性患者
査データと有意に関連した（データ補遺表 II，図 4 ）
：左
（ n ＝ 13 ）で，安静時脳血流量，脳血管反応性，併存危
；左中前
上前頭回由来の神経線維と処理速度（ r ＝ 0.45 ）
険因子の保有率に大きな差はなかった。T2 強調画像お
頭回，左縁上回，右縁上回由来の神経線維と TMT A
（そ
よび FLAIR 画像で，MMD 患者 10 例（ 43.5％）に白質
れぞれ r ＝ 0.43，0.43，0.48 ；
）左後帯状皮質由来の神経
高信号域が認められた。高信号域は症候性患者でも多
。ストループ検査の
線維と TMT B および A（ r ＝ 0.43 ）
。MMD 患者の総合知能指数
かった（ 7/10，p ＜ 0.05 ）
成績が高かった患者の右上前頭回，右中前頭回，左中帯
は平均 94 ± 13 であった。患者の神経心理学的評価の結
状皮質に由来する神経路の平均 FA 値は，対照群より有
果をデータ補遺表 I に要約する。症候性患者と無症候
意に高値であった。同様に，両側中前頭回，右前帯状
性患者において，総合知能指数，WAIS 検査のスコア，
皮質および左中帯状皮質に由来する神経路の平均 FA 値
その他の神経心理学的検査の項目に大きな差はなかっ
も，対照よりリーディングスパン検査の成績が高い患者
た。
で有意に高値であった。
灰白質の変化
考察
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 ）。
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，
白質の変化
成人 MMD は有用である。本研究は MMD 患者の両側後
白質神経路の空間的統計では，MMD 患者で広範囲に
帯状皮質密度の低下と，広範な白質領域における FA の
わたる有意な FA の低下と RD の上昇が認められた［そ
低下および RD の上昇を明らかにしたが，これらの変化
れぞれ全構造の 55.2％および 42.5％，図 2 ］
。FA およ
は年齢と関連していた。さらに，両側後帯状皮質密度は
び RD に変化があったボクセルも，有意な MD の上昇を
脳血行動態不全と有意に関連し，背外側前頭前野，帯状
示した。MD の上昇を示したボクセルは平均 FA 構造の
回，下頭頂小葉領域の白質神経路の平均 FA 値は神経心
20.9％を占めた。AD に関しては，多重比較の補正をし
理学的検査データと有意に関連した。
なかった場合，主に上縦束および帯状束で低下が認めら
後帯状皮質は覚醒，注意力，内向的思考，環境変化の
，補正した場合そのようなボ
れたが（未補正 p ＜ 0.05 ）
発見に関連する 15。後帯状皮質に限った局所的病変はほ
クセルは認められなかった。
とんど報告されていないため，神経認知機能への影響は
確率的トラクトグラフィーでも，MMD 患者の白質神経
いまだ不明である。脳卒中では知覚的な誤りよりも記
路の一部で平均 FA の低下が認められた。MMD 患者の各
憶障害が報告されているが，脳弓および脳梁に併存す
神経路のボクセル数は対照群と大きく変わらなかった。
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
V
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 ＝
Stroke-J-v10-i1-Full2.indd 12
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
16-Jun-15 10:27:11
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
13
表患者の特徴
Suzuki 分類
性別
脳血行動態不全
年齢，歳
臨床症状
WMH の場所
右
左
右
左
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
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
53
無症候性
なし
4
2
なし
なし
女
34
無症候性
なし
3
3
なし
なし
女
40
TIA
右前頭白質
3
2
中等度
中等度
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
女
46
無症候性
なし
4
4
なし
なし
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
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
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
併存症
高血圧
高血圧
高脂血症
糖尿病
高血圧
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
19
に関する詳細な情報は，RD および AD など方向に関連
る。本研究において，帯状回の容積減少は白質の結合
した DTI 指標を取り入れることで得られる。前者は髄
性の減少によるものと推測される。帯状回後部の脆弱性
鞘破損度を反映し，後者は軸索損傷とワーラー変性を
は，その高いエネルギー需要によって説明できるかもし
反映するとされている 26,27。本研究で認められた RD の
れない。他の脳部位と比べて後帯状皮質で消費される脳
優先的な上昇は，MMD における白質の主な病理的変化
20
血流と糖は 40％以上も多い。後帯状皮質は成人 MMD
が脱髄／髄鞘破損に起因することを表している可能性が
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
ある。本研究の探索的解析の結果，後ろから前に走る長
ると思われる。
い白質神経路で AD が低下する傾向が認められたが，多
21
白質は慢性虚血に弱い。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
22-24
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
。今回観察された白質の DTI 指標の変化もこれら
変性に伴う軸索腫脹を表す可能性がある。これらの
の変化を表す。主要な DTI 指標は，髄鞘形成，軸索膜
白質神経路は，他の神経路よりも虚血に弱いと想定さ
の健全性，軸索と膠細胞の密度，軸索方向の一貫性と関
れる。
る
連した脳の微細構造の変化に敏感である 25。一般的に，
本研究において，白質健全性の変化と，脳血行動態不
神経細胞または軸索の消失，髄鞘の変性は MD の上昇に
全に有意な関連はなかった。総合的にみて，白質構造
関連があるが，これは水分子の拡散を制限する細胞構造
の平均 FA 値と年齢に認められた相関は，虚血の重症度
が消失するためである。また，FA の低下にも関連があり，
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
これは高度に組織化された細胞構造（軸索および髄鞘）
唆する 7,8。あるいは MMD の慢性虚血により，加齢に伴
の整列度の低下によるものである。MD の変化より FA
う白質健全性の減少閾値が下がるかもしれない 21。本研
の変化領域が大きかったことは，FA がより白質の変化
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
に対して敏感であることを示す。髄鞘および軸索の損傷
たが，これは慢性虚血に対する脆弱性の局所的差異を示
Stroke-J-v10-i1-Full2.indd 13
16-Jun-15 10:27:11
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14
Stroke 日本語版 Vol. 10, No. 1
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
P
A
R
記憶の障害は MMD 患者の約 30％で認められた 2,3,28。本
L
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
R
L
R
L
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
R
L
R
0.05
L
0.0001
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
図1
p ＜ 0.05）。カラー
強調表示した
（ family-wise error 補正，
スケールは p 値を表す。
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
唆する。これらの結果は，血行再建手術の潜在的役割に
理学的データの欠如は，各々の比較で統計学的有意差の
ついて一定の方向性を示しているかもしれない。すでに
不足につながった可能性がある。第二に，前頭葉が介在
損傷を受けた灰白質および白質は，血行動態が改善して
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
も正常化する可能性は低いと考えられる。慢性虚血の持
的トラクトグラフィーに使用した。しかし，過去の機能
FA
RD
MD
AD
R
V
Stroke-J-v10-i1-Full2.indd 14
L 正常
有意な変化
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
図 2 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）
16-Jun-15 10:27:11
15
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
0.5
0.00041
r = 0.54
0.49
RD ( mm 2 S )
0.48
FA
0.47
0.46
0.45
0.44
0.0038
0.00037
0.0036
0.43
0.42
0.00034
0.45
0.5
0.6
0.55
0.65
0.7
0.75
0.00033
0.4
0.8
p < 0.01
0.00039
0.00035
0.41
0.4
r = ‒ 0.41
0.0004
p < 0.0001
0.45
0.5
0.00055
r = ‒ 0.26
0.00054
p = 0.07
0.6
0.65
0.7
0.75
0.8
0.00083
r = 0.10
0.00082
p = 0.50
0.00081
AD ( mm 2 S )
0.00053
MD ( mm 2 S )
0.55
帯状皮質の灰白質密度
帯状皮質の灰白質密度
0.00052
0.00051
0.0005
0.00049
0.0008
0.00079
0.0078
0.00077
0.00076
0.00048
0.00075
0.00047
0.4
0.45
0.5
0.55
0.6
0.65
0.7
0.75
0.8
0.00074
0.4
帯状皮質の灰白質密度
0.45
0.5
0.55
0.6
0.65
0.7
0.75
0.8
帯状皮質の灰白質密度
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，
（ 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。
図 3 p ＜ 0.0001）および放射拡散係数
AD：軸方向拡散係数，MD：平均拡散係数。
的 MRI の研究で側頭葉も作動記憶と関連することが明ら
る 35。最終的には，これが血行再建手術の最適な適応症
かになっている 33。第三に，白質の健全性は年齢および
の決定に役立つであろう。
34
性別に関連する。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
結論
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
MMD において，脳主幹動脈の狭窄閉塞性変化は主に
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
脳白質の微細構造に損傷を与え，実行機能，作動記憶，
処理速度
R
R
TMT-A
L
L
TMT-B-A
R
R
L R
L
P
0.001
Stroke-J-v10-i1-Full2.indd 15
ストループ
L
R
A
0.05
RST
L
R
L
R
L
R
L
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
図 4 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。
16-Jun-15 10:27:11
V
16
Stroke 日本語版 Vol. 10, No. 1
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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