Rustic global and widespread local white matter abnormalities in juvenile neuronal ceroid lipofuscinosis

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Juvenile
NCL
Robust global and widespread local white matter abnormalities in
juvenile neuronal ceroid lipofuscinosis
Principal investigator: Professor of radiology Taina Autti, HUS Medical Imaging Center, Radiology, University of Helsinki,
Helsinki University Hospital, Finland. Other investigators: Ulrika Roine, Timo Roine, Laura Åberg, Anna Tokola, Marja Balk,
Antti Hakkarainen, Minna Mannerkoski and Tuula Lönnqvist
Introduction:
Juvenile neuronal ceroid lipofuscinosis (CLN3) is a
progressive neurodegenerative lysosomal storage
disease of the childhood. It manifests with loss of
vision, seizures and loss of cognitive and motor
functions leading to premature death. Previous
magnetic resonance imaging (MRI) studies have
reported cerebral and cerebellar atrophy, progressive
hippocampal atrophy, thalamic signal intensity
alterations and decreased white matter volume in the
corona radiata.
Diffusion-weighted (DW) magnetic resonance
imaging (MRI) is a noninvasive method, which can be
used to investigate the white matter microstructure in
the brain by measuring the diffusion of water
molecules in white matter bundles. For the first time
in CLN3, we investigated global and local white
matter microstructure with DW-MRI in 14 children
with CLN3 (age 9.6±3.4, 71% males) and 14 control
subjects (age 11.2±2.3, 50% males). The acquisition
was repeated for the children with CLN3 two years
later (12 subjects, age 11.4±3.2, 67% males).
Discussion:
Here, we present the first diffusion weighted magnetic
resonance imaging study in juvenile neuronal ceroid
lipofuscinosis (CLN3).
Using both global and local approaches, we show
robust findings involving widespread decreases in FA
in CLN3. FA can be affected by dense packing of
nerve fibers, intact cell membranes, thickness of the
nerve fibers, myelinisation, orientation of the nerve
fibers and the amount of crossing fibers. As we also
found decreased planarity in CLN3, the differences in
FA could not be explained by changes in fiber
complexity, i.e. the amount of crossing fibers.
Moreover, diffusivity was in general increased in
CLN3 compared to control subjects, which is in
accordance with a previous study performed in
infantile NCL.
As conventional MRI is visually normal in CLN3 up
to an age of 10, we showed that DW-MRI is more
capable of detecting the microstructural changes
related to the disease.
We found no local or global differences between the
two CLN3 time points. In other words, the
microstructural changes were already present at the
time of the first scan (average age 9.6) and do not
progress rapidly in the prepubertal stage (the second
scan was acquired at an average age of 11.4).
Conclusion:
Our results indicate that the widespread
microstructural white matter abnormalities are present
already in less than 10 year old children with CLN3,
even though the conventional MRI is usually visually
normal under the age of 10. Furthermore, our results
suggest that the microstructural abnormalities do not
progress rapidly in the prepubertal stage. Further
studies are needed to detect whether these
abnormalities are present already at a younger age,
and to investigate the specific nature of these
differences with more detailed microstructural models.
Acknowledgements: Batten Disease Support & Research Association, Paulo Foundation, Finnish Brain
Foundation
Methods:
Investigation of global microstructural white matter
abnormalities with two methods
1) Whole-brain tractography: reconstruction of
nerve fibers in the brain with an advanced
tractography method: constrained spherical
deconvolution (CSD)
2) White matter tract skeleton: central voxels of
white matter tracts form a white matter tract
skeleton
Investigation of local microstructural white matter
abnormalities
1) Tract-based spatial statistics (TBSS) was used to
compare microstructural properties in the white
matter skeleton locally between the children with
CLN3 and control subjects
Microstructural properties:
Fractional anisotropy (FA): anisotropy
(directedness) of diffusion is generally higher in
coherent white matter fiber bundles as the water
molecules can diffuse more freely along the
white matter fiber than perpendicular to it.
Mean diffusivity (MD): average diffusion
distance in all directions
Axial diffusivity (AD): diffusivity along the
orientation of the white matter bundle
Radial diffusivity (RD): diffusivity
perpendicular to the orientation of the white
matter bundle
Planarity (CP): Provides knowledge about the
fiber complexity, i.e. crossing nerve fibers
Global results shown with both the
tractography and skeleton approach:
• Decreased global FA (p=0.000001) and
planarity values in CLN3
• Increased axial, radial and mean
diffusivity in CLN3
Similar results in the CLN3 children two
years later, but no significant difference
between the first and second time point.
Local results shown with TBSS:
• Widespread local decreases in FA (Fig.
1) for example in the corona radiata and
posterior thalamic radiation (both
p<0.0002)
• Widespread increases in mean, axial and
radial diffusivity (p<0.0002) (Fig. 2)
Figure 1. Local white matter abnormalities in fractional anisotropy (FA) investigated with tract-based spatial statistics.
Decreased FA values in CLN3 compared to controls illustrated in axial (A), coronal (B), and sagittal (C) slices.
Figure 2. Local increases in mean diffusivity (MD) investigated with tract-based spatial statistics.
Increased MD values in CLN3 compared to controls illustrated in axial (A), coronal (B), and sagittal (C) slices.