Title: Voxel based analysis in neuroferritinopathy determines clinical correlates of
disease severity. MJ Keogh et al.
Online Resources
Cerebellar Volume / Total IntraCranialVolume
0.14
0.13
0.12
0.11
0.10
0.09
0.08
0.07
0.06
Controls
Patients
Figure 1. Total cerebellar volumes as determined by serial ROI assessment of 3D-T1w axial slices and
normalised to total intra-cranial volume. The plot shows individual subject data points and mean cerebellar
volumes + standard deviation of the mean for patients and controls. There was a significant difference between
the two groups (p<0.001, unpaired t-test). Intra-rater reliability had a coefficient of variation of 3.6% as
determined from repeated measurements made on one dataset on three separate occasions each spaced 7 days
apart.
Figure 2. Image intensities and probability data in the dentate region in (a) qualitative T1w raw images, (b)
unsmoothed T1w GM segmented images, (c) smoothed T1w GM segmented images, (d) quantitative T2 maps,
(e) smoothed 8 voxel T2 VBR images.
Figure 3: Delineation of ROIs of regions detected to correlate with UDRS score on T1 images in a single patient
(a) head of caudate, (b) lateral GPi
Figure 4. Image intensities and probability data in the globus pallidus internus (a) qualitative T1w raw images,
(b) unsmoothed T1w GM segmented images, (c) smoothed T1w GM segemented images, (d) quantitative T2
maps, (e) smoothed 8 voxel T2 VBR images.
Figure 5: T1w slice through the cerebellum in a control subject and patient with neuroferritinopathy (top row).
Outlined in red are corresponding lateral aspects of the right dentate nuclei, with iron deposition and cavitation
seen in the patient. Bottom row: smoothed grey matter segmented slices through the same region showing that
the dentate nucleus in the patient is in a region with increased signal intensity.
Figure 6: T2w slice through the cerebellum in a control subject and patient with neuroferritinopathy (top row).
Outlined in red are corresponding lateral aspects of the right dentate nuclei, with iron deposition and cavitation
seen in the patient. Bottom row: quantitative T2 maps through the same region following smoothing which
show that the dentate nucleus in the patient is in a region with similar intensity to the control.
Figure 7. T1w image intensities and probability data of the caudate nucleus and lateral globus pallidus. Left –
caudate: (a) raw T1w image intensity, (b) unsmoothed grey matter segmented probability, and (c) smoothed
grey matter probability against patient UDRS score for 9 patients. Right – Globus pallidus internus: (a) raw
image intensity, (b) unsmoothed grey matter probability, and (c) smoothed grey matter probability against
patient UDRS score for all 10 patients. *p<0.05, ** p<0.005.
Cluster-level
P(corr)
Size
(voxels)
<0.001
244
<0.001
221
<0.001
1099
<0.001
<0.001
124
73
Voxel-level
p(uncor)
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
T-value
23.57
22.89
21.70
19.43
14.70
9.30
8.79
Coordinates
x
y
-16
14
-8
8
10
15
-18
Area
z
-52
-53
-14
-14
-7
-25
-26
side
-35
-33
-8
-8
-3
11
2
L
R
L
R
R
R
L
Posterior cerebellar lobe, dentate nucleus
Posterior cerebellar lobe, dentate nucleus
Left mid brain/substantia nigra
Right midbrain/substantia nigra
Right sub lobar extranuclear white matter
Right thalamus/pulvinar
Left thalamus
Table 1. Grey matter segmented VBM analysis of patients compared to controls (Pt > controls) (n=10). Voxel size 2x2x2 mm3. Only voxel level significance considered. A
threshold of T=7.088, P<0.05 (FWE) was used between groups.
Cluster-level
P(corr)
Size
(pixels)
<0.001
3474
Voxel-level
p(corr)
<0.001
6373
<0.0001
<0.0001
<0.0001
<0.0001
<0.001
<0.001
<0.001
188
21
23
<0.0001
<0.0001
<0.0001
<0.0001
T-value
19.31
18.46
12.79
15.42
14.86
14.24
11.72
10.53
9.94
Coordinates
x
y
-14
10
-16
-38
14
-29
16
-5
17
Area
z
-1
-1
-30
-60
-76
-68
-30
-91
-34
side
-5
-5
3
-31
-30
-28
4
-4
64
L
R
L
L
R
L
R
L
R
Lentiform nucleas/medial globus pallidus
Sub lobar, extra nuclear white matter
Thalamus
Posterior cerebellar lobe (Tuber)
Posterior cerebellar lobe (pyramis)
Posterior cerebellar lobe (Pyramis)
Thalamus
Occipital lobe, lingual gyrus
Pre central gyrus
Table 2. White matter segmented VBM analysis of patients compared to controls (controls > patients) (n=10). Voxel size 2x2x2 mm3. Only voxel level significance
considered. A threshold of T=7.17, P<0.05 (FWE) was used between groups.
Group
Controls (n=10)
Patients (n=10)
Dentate nucleus
T1w
T2w
Iron deposition
Cavitation
Iron deposition
Cavitation
1 (10%)
0 (0%)
N/A
N/A
10 (100%)
1 (10%)
10 (100%)
2 (20%)
Globus pallidus internus
T1w
T2w
Iron deposition
Cavitation
Iron deposition
Cavitation
4 (40%)
0 (0%)
N/A
N/A
10 (100%)
9 (90%)
10 (100%)
9 (90%)
Table 3. Clinical neuroradiology assessment of the dentate nucleus and globus pallidus internus of raw T1w and T2w images of patients and controls. Clinical interpretation
of relative T1w hyperintensity and hypointensity consistent with iron deposition and cavitation respectively, were recorded for both regions in patients and controls. T2w
hypointensity and hyperintensity consistent with iron deposition and cavitation respectively were recorded in patients only due to a lack of T2w images for controls.
Cluster-level
Voxel-level
P(uncorr)
Size
p(uncor)
(pixels)
Negative correlation with UDRS score
0.011
0.011
0.007
0.004
85
85
96
113
<0.0001
<0.0001
<0.0001
<0.0001
T-value
7.66
7.13
6.83
6.34
Coordinates
x
y
10
-10
16
-20
Area
z
8
9
-2
-6
side
14
10
4
5
R
L
R
L
Right caudate body
Left caudate body
Right lentiform and lateral GP
Left lentiform and lateral GP
Table 4:Grey matter weighted VBM correlation analysis with UDRS score (n=10). Voxel size 2x2x2 mm3. Only voxel level significance considered. An threshold of T=4.8,
p<0.001 uncorrected was used.
Study
Imaging
modality
Number
of
patients
Brain region
Globus
Pallidus
38%
hypointensity
Putamen
Caudate
Thalamus
Dentate
28%
hypointensity
14%
hypointensity
19%
hypointensity
95%
hypointensity
Substantia
Nigra
81%
hypointensity
McNeil
et al
2008[2]
T2*
21
Keogh
et al
2012[1]
T2*
9
Iron deposition
in infancy
-
Iron deposition
in adulthood
Iron deposition
in teens
-
Iron deposition
in infancy
McNeil
et al
2011[3]
T2
10
60% cavitation
10% cavitation
20%
hypointense
90%
hypointense
R2*
10
50%
cavitation,
10%
hypointense,
20% EOTT
No correlation
assessed
No R2*
correlation
with disease
10
Rim R2*
positive
correlation
with UDRS
T1
hyperintensity
in patients
-
T1
Rim R2*
negative
correlation
UDRS
T1
hyperintensity
in patients
50%
hypointense,
40%
hyperintense,
10% cavitation
-
T1
hyperintensity
in patients
T1
hyperintensity
in patients
This
study
Increasing
cavitation
correlates with
UDRS
Increasing T1
intensity
correlates with
UDRS
Cortex
Cerebellum
Motor
cortex only
affected
(71%)
Iron
deposition
in
adulthood
(motor
cortex only)
Motor
cortex and
lingual
gyrus shows
evidence of
iron
deposition
Cerebellar
atrophy
present
Table 5. A table outlining the results of previous neuroimaging studies in neuroferritinopathy together with the new findings from this study. All data relate to abnormal
findings in patients.
References
1.
Keogh MJ, Jonas P, Coulthard A, Chinnery PF, Burn J (2012) Neuroferritinopathy: a new inborn error
of iron metabolism. Neurogenetics 13:93-96
2.
McNeill A, Birchall D, Hayflick SJ, Gregory A, Schenk JF, Zimmerman EA, Shang H, Miyajima H,
Chinnery PF (2008) T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain
iron accumulation. Neurology 70:1614-1619
3.
McNeill A, Gorman G, Khan A, Horvath R, Blamire AM, Chinnery PF (2012) Progressive Brain Iron
Accumulation in Neuroferritinopathy Measured by the Thalamic T2* Relaxation Rate. AJNR Am J
Neuroradiol