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Whole-Brain Histogram and Voxel-Based Analyses of Diffusion Tensor Imaging in Patients with Leukoaraiosis: Correlation with Motor and Cognitive Impairment

Article · August 2007with46 Reads
DOI: 10.3174/ajnr.A0555 · Source: PubMed
Abstract
Cerebral white matter changes, termed leukoaraiosis (LA), appearing as areas of increased signal intensity in T2-weighted MR images, are common in elderly subjects, but the possible correlation of LA with cognitive or motor deficit has not been established. We hypothesized that histogram and voxel-based analyses of whole-brain mean diffusivity (MD) and fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) could be more sensitive tools than visual scales to investigate the clinical correlates of LA. Thirty-six patients of the Leukoaraiosis and Disability Study were evaluated with fluid-attenuated inversion recovery for LA extension, T1-weighted images for volume, and DTI for MD and FA. The extent of LA was rated visually. The normalized total, gray, and white matter brain volumes were computed, as well as the 25th percentile, 50th percentile, kurtosis, and skewness of the MD and FA maps of the whole brain. Finally, voxel-based analysis on the maps of gray and white matter volume, MD, and FA was performed with SPM2 software. Correlation analyses between visual or computerized data and motor or neuropsychologic scale scores were performed using the Spearman rank test and the SPM2 software. The visual score correlated with some MD and FA histogram metrics (P<.01). However, only the 25th and 50th percentiles, kurtosis, and skewness of the MD and FA histograms correlated with motor or neuropsychologic deficits. Voxel-based analysis revealed a correlation (P<.05 corrected for multiple comparisons) between a large cluster of increased MD in the corpus callosum and pericallosal white matter and motor deficit. These results are consistent with the hypothesis that histogram and voxel-based analyses of the whole-brain MD and FA maps are more sensitive tools than the visual evaluation for clinical correlation in patients with LA.
Figures
ORIGINAL
RESEARCH
Whole-Brain Histogram and Voxel-Based
Analyses of Diffusion Tensor Imaging in Patients
with Leukoaraiosis: Correlation with Motor and
Cognitive Impairment
R. Della Nave
S. Foresti
A. Pratesi
A. Ginestroni
M. Inzitari
E. Salvadori
M. Giannelli
S. Diciotti
D. Inzitari
M. Mascalchi
BACKGROUND AND PURPOSE: Cerebral white matter changes, termed leukoaraiosis (LA), appearing as
areas of increased signal intensity in T2-weighted MR images, are common in elderly subjects, but the
possible correlation of LA with cognitive or motor deficit has not been established. We hypothesized
that histogram and voxel-based analyses of whole-brain mean diffusivity (MD) and fractional anisotropy
(FA) maps calculated from diffusion tensor imaging (DTI) could be more sensitive tools than visual
scales to investigate the clinical correlates of LA.
MATERIALS AND METHODS: Thirty-six patients of the Leukoaraiosis and Disability Study were evalu-
ated with fluid-attenuated inversion recovery for LA extension, T1-weighted images for volume, and
DTI for MD and FA. The extent of LA was rated visually. The normalized total, gray, and white matter
brain volumes were computed, as well as the 25th percentile, 50th percentile, kurtosis, and skewness
of the MD and FA maps of the whole brain. Finally, voxel-based analysis on the maps of gray and white
matter volume, MD, and FA was performed with SPM2 software. Correlation analyses between visual
or computerized data and motor or neuropsychologic scale scores were performed using the Spear-
man rank test and the SPM2 software.
RESULTS: The visual score correlated with some MD and FA histogram metrics (P .01). However,
only the 25th and 50th percentiles, kurtosis, and skewness of the MD and FA histograms correlated
with motor or neuropsychologic deficits. Voxel-based analysis revealed a correlation (P .05 corrected
for multiple comparisons) between a large cluster of increased MD in the corpus callosum and
pericallosal white matter and motor deficit.
CONCLUSIONS: These results are consistent with the hypothesis that histogram and voxel-based
analyses of the whole-brain MD and FA maps are more sensitive tools than the visual evaluation for
clinical correlation in patients with LA.
C
erebral white matter changes, appearing as hypoattenu-
ated areas in CT scans and as hyperintense areas in T2-
weighted MR images, are common in elderly subjects and have
been termed leukoaraiosis (LA). The correlation of LA with
arterial hypertension and history of stroke and some neuro-
pathologic studies suggest a small vessel alteration as the un-
derlying cause of LA.
1-3
However, LA also correlates with aging
and is a nonspecific finding, because it reflects different his-
topathologic changes, such as demyelination, loss or increase
of glial cells, vacuolization (spongiosis), apoptosis of oligo-
dendrocytes, and wallerian degeneration.
3,4
The possible cor-
relation of LA with cognitive decline or motor deficit has been
investigated using visual or computerized methods to assess
the LA extent.
5-16
Diffusion-weighted imaging (DWI) and dif-
fusion tensor imaging (DTI) are MR techniques sensitive to
changes in the diffusion properties of water protons in terms
of apparent diffusion coefficient (ADC), mean diffusivity
(MD), or fractional anisotropy (FA). Previous studies using
region of interest measurements have demonstrated that MD
and FA in patients with LA are altered not only in the areas
exhibiting signal intensity changes in T2-weighted images but
also in the normal-appearing white matter.
17,18
Using whole-
brain histogram analysis of ADC, it is possible to obtain a
quantitative global assessment of the tissue changes associated
with LA.
19,20
Recently, voxel-based analysis has also emerged
as a powerful tool to investigate regional changes of the vol-
ume, ADC, MD, or FA of the whole brain in a number of
diseases.
21-24
We hypothesized that histogram and voxel-
based analyses of whole-brain MD and FA maps calculated
from DTI could be more sensitive tools than visual scales to
investigate the clinical correlates of LA. Accordingly, we used
histogram and voxel-based analyses to measure the global and
regional changes in 36 patients with LA belonging to the Leu-
koaraiosis and Disability (LADIS) Study who were examined
with DTI and correlated the findings obtained with these
methods, with 1 visual scale, and with the results of quantita-
tive motor and neuropsychologic evaluations.
Materials and Methods
The LADIS Study
The LADIS Study is a longitudinal multicentric European study,
which aims: 1) to establish whether LA and its progression over time
play a role as an independent determinant of the transition from
functional autonomy to disability in elderly subjects; 2) to confirm
Received October 16, 2006; accepted after revision November 16.
From the Radiodiagnostic Section, Department of Clinical Physiopathology (R.D.N., S.F.,
A.P., A.G., M.M.), Clinica Neurologica III, Department of Neurology and Psychiatry (M.I.,
E.S., D.I.), and Department of Electronics and Telecommunications (S.D.), University of
Florence, Florence, Italy; Medical Physics (M.G.), Azienda Ospedaliera Universitaria Pisana,
Pisa, Italy.
Address correspondence to Mario Mascalchi, Sezione di Radiodiagnostica, Dipartimento di
Fisiopatologia Clinica, University of Florence, Florence, Italy; e-mail: m.mascalchi@dfc.
unifi.it
Indicates article with supplemental on-line table.
DOI 10.3174/ajnr.A0555
BRAIN ORIGINAL RESEARCH
AJNR Am J Neuroradiol 28:1313–19 Aug 2007 www.ajnr.org 1313
whether LA and its progression independently predict death, cardio-
vascular events, and dementia; 3) to examine whether progression of
LA parallels the deterioration of specific motor and cognitive perfor-
mances; and 4) to evaluate whether LA has an impact on quality of
life.
25
The enrollment criteria of the LADIS Study are detailed else
-
where
25
and include the following: 1) age between 64 and 84 years; 2)
changes of the cerebral white matter on MR imaging of any degree;
and 3) no or mild disability. The study design establishes a core MR
imaging protocol including T1 and T2-weighted fluid-attenuated in-
version recovery (FLAIR) images that is shared by the 11 participating
centers, whereas DWI, DTI, or magnetization transfer techniques are
used by selected centers to further characterize tissue changes.
Subjects
The study was approved by our institutional review board. Thirty-six
consecutive patients (21 women and 15 men; mean age, 77 4.5
years; age range, 69 84 years) belonging to the LADIS Study were
examined. None of them had evidence of corticosubcortical infarcts.
All 36 of the patients were evaluated according to the LADIS protocol,
which includes a functional and clinical assessment.
25
In particular, 1 of the authors with 6 years of clinical experience in
geriatric neurology (M.I.) evaluated all of the patients for motor def-
icit with a modified Short Physical Performance Battery (SPPB),
26
in
which the original “8-foot-walk” was substituted by a “4-m-walk”
test, and with 2 simple measures of gait and balance (gait velocity and
single-leg stance time).
4
Increasing deficits correspond with lower
scores in the SPPB, lower gait velocities, and shorter single-leg stance
times.
An extensive neuropsychologic examination was performed in all
of the patients by another author (E.S.) with 7 years of clinical expe-
rience. The neuropsychologic battery included global cognitive tests
(Mini Mental State Examination; MMSE)
27
; executive function tests,
such as Stroop
28
and Trail Making Test
29
; and tests of the Vascular
Dementia Assessment Scale,
30
evaluating attentive functions such as
the Maze Task, Digit, and Verbal Fluency Test. Increasing deficit cor-
responds with lower scores on the MMSE, Digit, and Verbal Fluency
Tests and higher scores on the Stroop and Trail Making Tests and
Maze Task.
The results of the motor and neuropsychologic assessment of the
36 patients are reported in Table 1. All of the patients gave their
informed consent to participate in the study.
MR Acquisition Protocol
All of the examinations were performed on a 1.5T system (Intera,
Philips Medical System, Best, the Netherlands) equipped with 30-
mT/m gradients and a sensitivity-encoding (SENSE) head coil.
MR Imaging. After scouts, the examination protocol included ax-
ial 3D T1-weighted turbo gradient-echo (TR 25 ms; TE 4.6 ms;
flip angle 30°; FOV 256 mm; matrix size 256 256; 160
contiguous sections; section thickness 1 mm; NEX 1) images and
axial T2-weighted images, which were obtained with a FLAIR se-
quence (TR 6000 ms; TE 120 ms; inversion time 2000 ms;
FOV 250 mm; matrix size 256 256; 24 sections; section gap
0.5 mm; section thickness 5 mm; turbo factor 24; SENSE fac-
tor 1.75; NEX 2).
DTI. A diffusion-weighted single-shot echo-planar imaging se-
quence (TR 4432 ms; TE 89 ms; FOV 256 mm; matrix size
128 128; 26 sections; section thickness 5 mm; no gap; NEX 2)
was acquired on axial plane with diffusion sensitizing gradients ap-
plied along 32 noncollinear directions using b value of 0 (B
0
image)
and 1000 s/mm
2
. Maps of MD and FA were calculated from the dif
-
fusion tensor images by Philips commercially available software.
Image Analysis
Visual Assessment. One operator (A.G.) with 5 years of experi-
ence in clinical MR imaging evaluated the FLAIR images of the 36
patients to rate LA extent by using the visual scale proposed by Faze-
kas et al.
31
The scale has a range between 0 and 6 (On-line Table) and
showed a very good interoperator agreement in a previous study.
19
In
addition, the operator was requested to specifically assess the signal
intensity of the corpus callosum in FLAIR images.
Brain Volume Analysis. To explore possible correlation between
atrophy and clinical parameters, the SIENAX method,
32
part of FSL
3.3 (FMRIB, Oxford, UK),
33
was applied to each subject T1-weighted
acquisition to estimate the total, gray matter, and white matter brain
volume, normalized for head size of the subject.
Histogram and Voxel-Based Analyses. The methods for histo-
gram analysis were reported previously.
24
Using a custom-made soft
-
ware (available on request) the 25th and 50th (median) percentile
values, kurtosis, and skewness of the whole-brain MD and FA histo-
grams were computed. Kurtosis describes how sharply peaked a his-
togram is compared with the histogram of a normal distribution.
Accordingly, whereas a normal distribution has a kurtosis of 0, a more
peaked histogram has a positive kurtosis value. Skewness describes
the degree of asymmetry of a histogram: a perfectly symmetric histo-
gram has a skewness of 0, a histogram with a long right tail has a
positive skewness, whereas a negative skewness is due to the presence
of a long left tail. The methods for voxel-based morphometry (VBM)
and voxel-based analyses of the MD and FA maps were reported
previously.
24,34
Statistical Methods
The nonparametric Spearman rank test was used to assess possible
correlation of the visual scores with the brain volumes and histogram
parameters derived from MD and FA maps. The same test was also
used to investigate possible correlation between the above MR vari-
ables and the clinical scale scores. For all of these analyses, the signif-
icance threshold was set at P .01.
The correlation tool of the SPM2 software (Wellcome Depart-
ment of Imaging Neuroscience, London, UK) was used to correlate
maps of T1, MD, and FA (decreased gray matter, decreased white
matter, increased MD, and decreased FA) with the parametric motor
Table 1: Results of the quantitative motor and neuropsychologic
evaluations in 36 patients with LA
Variable Mean SD Range
Normal
Values
SPPB 8 2.5 4–12 12*
Usual gait velocity, m/s 3 1 1–4 1.2 0.2†
Single-leg stance time, s 15 10.8 1–41 17.2 4.1†
MMSE 26 3.4 17–30 27
Stroop Test 57 25.3 26–158 NA
Trail Making Test, s 90 49 33–225 NA
Maze Task, s 9 7 2–33 NA
Digit Test 13 4.3 2–22 NA
Verbal Fluency Test 15 4.8 6–25 NA
Note:—SPPB indicates Short Physical Performance Battery; MMSE, Mini Mental State
Examination; LA, leukoaraiosis; NA, not available.
* From reference 26.
From reference 8.
1314 Della Nave AJNR 28 Aug 2007 www.ajnr.org
and neuropsychologic data. Statistical significance was set at P .05
corrected for multiple comparison using the false discovery rate
method.
35
Because previous studies reported a correlation between
atrophy of the corpus callosum and gait disorder and cognitive defi-
cits in patients with LA,
36-38
we also performed a correlation between
FA maps and motor scores and between MD and FA maps and cog-
nitive scores using a small volume correction. This was accomplished
by selecting the voxels of interest corresponding with the Talairach-
based mask of the corpus callosum provided by the Wake Forest Uni-
versity PickAtlas (Winston Salem, NC).
39
Results
Figure 1 shows FLAIR images and corresponding whole-brain
MD and FA histograms in 2 representative patients with mild
(visual score 2) and extensive (visual score 6) LA. The results
of visual assessment of LA; the global, gray, and white matter
volumes; and the metrics of the MD and FA whole-brain his-
tograms in the 36 patients are detailed in Table 2.
Hyperintensity of the corpus callosum in FLAIR images
was observed in 2 patients only. The visual score correlated
with some DTI metrics, including the 25th percentile of MD
and skewness and kurtosis of FA, but not with any of the brain
volumes (Table 3).
The correlation of the visual score, brain volumes, and the
metrics of the MD and FA whole-brain histograms with the
clinical scales scores are detailed in Table 4. No significant
correlation was observed between visual score or brain vol-
umes and any of the clinical parameters. The 25th and 50th
percentiles of MD and the kurtosis and skewness of FA histo-
grams correlated with motor and cognitive deficits. No corre-
lation between gray or white matter volume and motor or
cognitive scores were observed in the VBM analysis.
Table 5 reports the clusters of MD and FA changes signifi-
cantly correlated with clinical parameters. A correlation be-
tween a wide cluster of MD change in the corpus callosum and
pericallosal white matter and the SPPB score and the usual gait
Fig 1. AD, Whole-brain MD (A) and FA (B) histograms in a patient with low (n 2) visual score of LA (continuous line), as shown by corresponding FLAIR images (C), and in a patient
with high (n 6) visual score of LA (dashed line), as shown by corresponding FLAIR images (D).
A and B, The patient with the higher visual score shows higher 50th percentile (85.9 vs. 84.7) and lower kurtosis and skewness of the MD histogram (A) and lower 50th percentile (0.165
vs. 0.226) and higher kurtosis and skewness of the FA histogram (B) compared to the patient with lower visual score.
AJNR Am J Neuroradiol 28:1313–19 Aug 2007 www.ajnr.org 1315
velocity was observed (Fig 2). A correlation between smaller
clusters of FA in the corpus callosum and the same measure-
ments of motor performance was observed only when small
volume correction was used (Fig 3). No correlation with the
scores of the cognitive tests was observed for voxel-based anal-
ysis of MD or FA maps without or with small volume
correction.
Discussion
The clinical relevance of LA with respect to cognitive and mo-
tor functions is not established, and some discrepancy might
in part arise from the different methods proposed for the as-
sessment of LA.
40
Several visual scales were proposed to quantify the extent of
LA
40
with variable score spans and interobserver reproducibil
-
ity. Overall, no or weak correlation with quantitative measure-
ments of cognitive deficit was observed in cross-sectional
studies evaluating a small sample of patients,
5-7,13-15
whereas
on greater sample sizes, typically of hundreds of patients, cor-
relation among the extent of LA, global cognitive impairment,
executive dysfunctions, and slowing of mental processing was
observed.
9,41
Similar results were obtained when the extent of
LA was calculated using a volumetric approach.
6,16,42
Few
cross-sectional studies reported a correlation between the ex-
tent of LA evaluated visually or with computation of LA vol-
ume and gait or motor deficit.
8,11,12,16
We failed to identify any correlation between the extent of
LA and clinical scores of motor or cognitive deficit in our small
cross-sectional study. This confirms that visual scales are not
very sensitive to the clinical counterpart of LA.
16
It is noteworthy that the visual and volumetric approaches
do not assess the severity of the tissue structural changes asso-
ciated with LA and discard the abnormalities in the normal-
appearing white matter in patients with LA. Hence, methods
assessing the whole brain, including the normal-appearing
white matter and the gray matter, could be more sensitive.
Histogram and voxel-based analyses are 2 methods suitable
for this purpose, which, despite their respective advantages
and drawbacks, share a very robust statistical power. In fact,
both enable analysis of many thousand of voxels compared
with the few voxels usually sampled using small regions of
interest.
In the histogram approach, an effective graphic represen-
tation of the whole-brain distribution of the parameters being
investigated, such as MD or FA, is provided. It is noteworthy
that histogram metrics along with evaluation of the entire
brain reflect not only extent but also severity of the damage
associated with LA. Whole-brain histograms were initially
used to investigate correlates of disability in multiple sclerosis
(MS), which is a common inflammatory white matter dis-
ease.
43
The main limitation of histogram analysis is the loss of
the topographic information, which, however, can be regained
if the histogram calculation is preceded by segmentation based
on anatomic landmarks.
44
Voxel-based analysis was initially developed to assess
whole-brain T1-weighted images (VBM) searching for loss of
volume of the gray matter and white matter.
34
VBM has found
application in a number of diseases to determine loss of bulk of
the gray and white matter.
21,45
Voxel-based analysis can also
be used to assess other MR parameters, such as the ADC, MD,
and FA,
22-24
which assess the structural integrity of the re
-
maining nervous tissue. The voxel-based approach overcomes
the limitations of the region of interest approach, namely the
operator dependence and the a priori knowledge bias, and
maintains the regional information. Its main drawback is that
the method is suited for analyzing groups of patients and not
the single subject.
To the best of our knowledge, our is the first study investi-
gating motor and cognitive correlates of LA using whole-brain
histogram and voxel-based analyses of DTI. Overall, our
whole-brain histogram DTI results are in line with those re-
ported in MS.
43
In particular, we observed a correlation be
-
tween increasing extent of the visually appreciable LA, on the
one hand, and increase of the 25th and 50th percentiles com-
bined with decreased kurtosis and skewness of the MD and
decrease of the 25th and 50th percentiles combined with in-
creased kurtosis and skewness of the FA, on the other hand.
The interpretation of these histogram metrics was addressed
previously in a study of MS and can be reasonably applied to
our findings.
43
In particular, because normal gray and white
matter show very similar MD values, the corresponding
whole-brain MD histogram shows a bell-shaped curve point-
ing to a distribution around a central bin. The increased MD of
the white matter associated with LA determines along with
increase of the 25th and 50th percentiles a decrease of the
Table 2: Results of visual assessment, brain volumes, and MD and
FA histogram parameters in 36 patients with LA
Variable Mean SD Range
Fazekas scale 4 1.3 2–6
Normalized brain volume, mm
3
1,418,885 114,852 1,135,915–1,649,413
Gray matter, mm
3
678,719 177,773 430,615–1,325,915
White matter, mm
3
740,166 242,657 83,385–1,106,288
Whole-brain MD, 10
3
mm
2
/s
25th percentile 77.9 2.9 73.3–86.0
50th percentile 89.3 3.8 83.4–98.7
Skewness 2 0.3 1–3
Kurtosis 8 1.8 5–13
Whole-brain FA
25th percentile 0.13 0.02 0.10–0.18
50th percentile 0.21 0.02 0.16–0.26
Skewness 1 0.2 1–2
Kurtosis 5 0.8 4–7
Note:—LA indicates leukoaraiosis; MD, mean diffusivity; FA, fractional anisotropy.
Table 3: Spearman rank correlation (
) values among visual score,
brain volumes, and histogram parameters in 36 patients with LA
Variable Fazekas Scale,
P
Normalized brain volume 0.06
Gray matter 0.17
White matter 0.04
Whole-brain MD
25th percentile 0.47 .003
50th percentile 0.36
Skewness 0.30
Kurtosis 0.23
Whole-brain FA
25th percentile 0.15
50th percentile 0.27
Skewness 0.46 .003
Kurtosis 0.54 .001
Note:—LA indicates leukoaraiosis; MD, mean diffusivity; FA, fractional anisotropy.
1316 Della Nave AJNR 28 Aug 2007 www.ajnr.org
kurtosis (the curve becomes less peaked) and of the skewness
(the curve becomes less asymmetric) of the histogram. On the
contrary, the distribution of normal gray and white matter
anisotropy is very different, with lower values for the gray
matter and higher values for the white matter. Hence, FA his-
tograms created from images containing gray and white mat-
ter are necessarily the results of the superimposition of 2 dif-
ferent bell-shaped curves. The decreased FA of the white
matter associated with LA determines along with a decrease of
the 25th and 50th percentiles a relative increase of the low FA
values with increased kurtosis (the curve becomes more
peaked) and of the skewness (the curve becomes more asym-
metric) of the histogram.
More interestingly, we found correlation between histo-
gram metrics and quantitative clinical scores describing the
motor and cognitive impairment observed in patients with
LA. In particular, whereas our data confirm those of a previous
region of interest study, which showed correlation between
MD in the normal-appearing white matter and executive dys-
function in patients with LA,
13
they reveal a correlation with
motor dysfunction not reported previously. The fragmentary
correlation between the MD and FA histogram metrics and
Table 4: Spearman rank correlation (
) values between visual score of LA, brain volumes, MD and FA histogram metrics, and motor and
neuropsychologic scores
Variable SPPB
Usual Gait
Velocity, m/s
Single-Leg Stance
Time, s MMSE
Stroop
Test
Trail-Making
Test
Maze
Task Digit
Verbal
Fluency
Fazekas scale 0.18 0.15 0.26 0.19 0.13 0.08 0.11 0.23 0.28
Normalized brain volume 0.38 0.02 0.22 0.05 0.09 0.08 0.18 0.15 0.04
Gray matter 0.01 0.11 0.11 0.10 0.14 0.07 0.17 0.10 0.06
White matter 0.28 0.26 0.04 0.02 0.02 0.14 0.29 0.24 0.05
Whole-brain MD
25th percentile 0.21 0.32 0.48 0.28 0.51 0.30 0.32 0.30 0.46
(P .006) (P .001) (P .004)
50th percentile 0.15 0.20 0.35 0.16 0.54 0.31 0.30 0.31 0.44
(P .001) (P .007)
Skewness 0.28 0.34 0.16 0.34 0.23 0.42 0.44 0.45 0.13
(P .008) (P .006)
Kurtosis 0.24 0.25 0.16 0.35 0.17 0.37 0.38 0.40 0.06
Whole-brain FA
25th percentile 0.02 0.00 0.01 0.24 0.11 0.01 0.17 0.08 0.10
50th percentile 0.04 0.10 0.09 0.18 0.17 0.06 0.09 0.01 0.17
Skewness 0.18 0.35 0.21 0.15 0.26 0.14 0.18 0.28 0.41
Kurtosis 0.22 0.39 0.27 0.21 0.32 0.18 0.21 0.32 0.46
(P .005)
Note:—LA indicates leukoaraiosis; MD, mean diffusivity; FA, fractional anisotropy; SPPB, Short Physical Performance Battery; MSSE, Mini Mental State Examination.
Table 5: Correlations between voxel-based analysis of MD and FA maps and motor assessment
Correlation
Cluster Extent,
mm
3
P*
t
Score
Z
Score
Coordinates (Local
Maxima)
Areasxyz
MD, SPPB 45648 0.048 5.58 4.67 16 24 34 Corpus callosum and pericallosal white matter
MD, usual gait velocity 16536 0.043 5.14 4.37 6 14 20 Corpus callosum and pericallosal white matter
FA, SPPB 824 0.019 4.09 3.65 6 28 20 Corpus callosum splenium
FA, usual gait velocity 572 0.025 3.72 3.39 6 0 24 Corpus callosum genu
Note:—MD indicates mean diffusivity; FA, fractional anisotropy; SPPB, Short Physical Performance Battery.
* P is false discovery rate corrected for multiple comparisons.
Fig 2. A–C, SPM2 “glass brain” representation showing large clusters in the corpus callosum and pericallosal white matter of significant (P 0.05, corrected for multiple comparison
by false discovery rate method) correlation between increasing MD value and scores of motor deficit (usual gait velocity in A; SPPB in B ) in patients with LA. Superimposition of the same
cluster demonstrated in B onto T1 template (C ).
AJNR Am J Neuroradiol 28:1313–19 Aug 2007 www.ajnr.org 1317
the motor and cognitive scores in our study could suggest
by-chance correlation. However, we used a conservative sta-
tistical test for correlation, all of the correlations were ex-
pected, and they are in line with previous observations in stud-
ies using visual or volumetric assessment of LA.
The main result of the voxel-based analysis that we per-
formed is the strong correlation between a wide cluster-in-
creased MD in the corpus callosum and pericallosal white
matter fibers and 2 indices of motor impairment. Although a
correlation between corpus callosum atrophy and motor dis-
ability was reported previously in patients with LA,
36,37
we did
not find correlation between motor score and any cluster in
the voxel-based analysis of T1-weighted images that we per-
formed. On the other hand, in line with general sparing of the
signal intensity of the corpus callosum in patients with LA,
46
callosal signal intensity abnormality was observed in only 2 of
our 36 patients. This indicates that we probably demonstrated
a microscopic and presumably early damage of the callosal
white matter fibers. We submit that this finding could explain
the pathophysiology of motor disturbances in LA and, in par-
ticular, the similarity of the clinical motor disturbance of pa-
tients with LA with that of patients with so called “normal
pressure hydrocephalus,” in which impingement of the cal-
losal fibers on the falx cerebri caused by dilated ventricules is
assumed to be responsible for the gait “apraxia,” which is re-
versed by CSF shunt and decreased ventricular size.
47
Al
-
though a correlation between the regional atrophy of the cor-
pus callosum and mental slowing and executive deficits was
reported recently in the entire group of the patients enrolled in
the LADIS protocol,
38
we failed to identify any correlation in
the voxel-based analysis of the maps of the gray and white
matter volume, the MD, and the FA with the neuropsycho-
logic tests scores. We speculate that this negative result funda-
mentally reflects the small sample size in our study.
We recognize some limitations of our study. First, we ex-
amined a relatively small number of subjects in our study.
Hence, the results that we obtained have to be considered as
preliminary to future studies on larger samples of patients.
Second, we evaluated possible signal intensity changes in the
corpus callosum on axial FLAIR images only. This could de-
termine an underestimation of such signal intensity changes,
which are better demonstrated on sagittal or coronal planes.
Third, we did not examine healthy age-matched control sub-
jects. However, many studies using DWI and DTI have dem-
onstrated the progressive mild modifications of the diffusion
properties of the water protons in the aging brain with in-
creased ADC and MD and decreased FA, which are far less
pronounced than those encountered in patients with LA.
48-50
Fourth, the methodology that we used is not widely available.
However, DTI is becoming a fundamental component of MR
imaging equipment, and MD and FA histogram metrics
showed excellent imaging-reimaging and interimaging unit
reproducibility.
51
The software for image processing and
SPM2 are available from the Internet, and the software for
computation of histogram metrics is available on request.
In conclusion, our study confirms the hypothesis that the
results of whole-brain histogram and voxel-based analyses of
the damage associated with LA demonstrated by DTI are more
closely related to the actual clinical deficit than the visual as-
sessment. For this reason, application of these analysis meth-
ods to the evaluation of LA should be encouraged, especially in
the context of future pharamacologic trials for LA. In particu-
lar, voxel-based analysis shows that the motor impairment in
patients with LA is strongly correlated with increased MD in
the corpus callosum and pericallosal white matter fibers.
Voxel-based analysis of MD and FA maps on larger samples
has the potential to clarify many physiopathologic aspects of
LA.
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AJNR Am J Neuroradiol 28:1313–19 Aug 2007 www.ajnr.org 1319
  • ...In the past decade, studies have been focused on the correlations between the age-related WMLs and agerelated decline in various functional abilities in the elderly aged people. Accumulating evidence showed a great association and correlation between WMLs and functional disabilities that include gait and balance dysfunction ( Baezner et al., 2008;Baloh et al., 2003;Bhadelia et al., 2009;de Laat et al., 2010;Murray et al., 2010), falls (Blahak et al., 2009), decline in information processing speed and executive function ( Prins et al., 2005), and impairment of attention, memory, and global cognitive performance (Della Nave et al., 2007;Prins et al., 2005), in normal old people. In a longitudinal study, Baloh and coworkers measured visual acuity, vestibulo-ocular response, pure-tone hearing thresholds, vibration sense, deep tendon reflexes, and gait/balance performance in 59 normal older subjects with averaged age of 78.5 on entry ( Baloh et al., 2003). ...
  • ...However, the spatial variation of WM pathology among subjects is high ( Thiebaut de Schotten et al., 2011;Muller et al., 2009;Lipton et al., 2012;Kim et al., 2013), and thus voxel-by-voxel statistical analysis of FA images may not be appropriate in the assessment of neurodegenerative diseases. A few studies have addressed such limitation of voxel-wise analysis by instead adopting a histogram approach to characterize and compare shapes of WM FA distributions between patients and healthy subjects ( Benson et al., 2007;Lipton et al., 2008;Nave R et al., 2007). However, these comparisons have been limited to two-sample t-tests comparing patients' and controls' estimated moment summary statistics, such as mean, variance, skewness, and kurtosis of individual subjects' histograms of brain-wide image distributions ( Benson et al., 2007). ...
  • ...Fractional anisotropy (FA) and the mean (MD), axial (AD) and transverse (TD) diffusion measures were subsequently computed[24]. Note that these DTI based measures have been shown to be more sensitive to tissue abnormalities than the typical visual evaluation of WM hyperintensities observed in conventional MRI data[25][26][27]. c A population-based DTI atlas in MNI space was constructed[20,28]to drive the tensor based affine[29]and non-affine[30]coregistration techniques. ...