Corticospinal Degeneration in
Amyotrophic Lateral Sclerosis
(ALS)
Investigation with DTI
Sarah Carrington Heidi Johansen-Berg Emma Sillery
FMRIB
What is ALS?
• Progressive neuromuscular disease
• Incidence ~ 2/10,000
• Charcot & Joffroy (1869) – Involves both
upper (UMN) and lower motor neurons
(LMN)
• Associated with dementia in ~3.5% of
cases
Lower vs. upper motor neuron
syndromes
• Progressive • Primary Lateral
Muscular Atrophy Sclerosis (PLS)
(PMA) • ~1% of Patients
• ~10% of patients • Symptoms
• Symptoms include:
include: 1. Hyper-reflexia
1. Muscular 2. Babinski Sign
weakness
3. Spasticity
2. Muscular wasting
3. Fasciculations
Pathology of ALS
• Axonal degeneration, gliosis, and myelin pallor in the
posterior limb of the internal capsule
• Loss of large pyramidal motor neurons (Betz cells) and
cortical degeneration
• BUT ALL OF THESE SIGNS ARE
FOUND POST MORTEM
• As yet, there is no objective and sensitive marker of
UMN involvement.
Aims and hypotheses: Part 1
• To assess the integrity of the corticospinal tract (CST)
• Diffusion Tensor Imaging to investigate the degree of
anisotropic diffusion
• In white matter, the principle direction
of diffusion corresponds well with the
orientation of major fibres in each voxel
• If CST is degenerated in ALS patients, would expect
less anisotropy of diffusion compared with controls
– Ellis et al., 1999; Toosey et al., 2003
Fractional Anisotropy
(FA)
• A value that reflects the extent to which diffusion
can be accounted for by anisotropic diffusion
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Methods: Part 1
• 9 patients – 7 males
– 3 with PLS, 1 with PMA, 5 with ALS
– Assessed on the Amyotrophic Lateral Sclerosis
Functional Rating Scale
• 7 controls – 5 males
• DTI – 63 volumes
– 3 without diffusion weighting
– 60 diffusion gradients with different weightings
• Structural – T1.5 – converted into standard
space
Analysis: Part 1
• Registration and motion correction
• FA calculated for each voxel – FA map
• Converted into standard space
• Smoothed with 3mm kernel
• FA map for each individual was then
merged into one file
• Used T-tests to look for areas where FA
was significantly different between patients
and controls
Results:
Part 1 – Areas where patients have
reduced FA relative to controls
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Part 2: Tractography
• By following the direction of diffusion, it is
possible to ‘reconstruct’ major fibre pathways
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• Probabilistic tractographic algorithm creates a
quantitative reconstruction of these tracts
Part 2 - tractography
• Investigating projections from the internal
capsule (z=2) to the primary motor cortex
• 4 main measures
1. The mean probability that voxels are connected to M1
2. Intensity – the probability that the voxel maximally connected
to M1 reaches the target
3. Cross-sectional volume of the CST in the internal capsule
4. Cross-sectional volume of the high probability core of the CST
in the internal capsule
• If the CST is degenerated in patients with ALS,
should be less able to track along it
The mean probability and intensity of
connection to M1 appears decreased in
patients compared with controls
1
Mean probability of connection
0.25
0.2 0.95
Intensity
0.15 0.9
to M1
0.1 0.85
0.05 0.8
0 0.75
Controls Patients Controls Patients
Group Group
Non-significant (p<0.05)
Thresholded volume of internal capsule is
smaller in patients than controls
27.8
27.6
Thresholded volume
27.4
27.2
27
26.8
26.6
26.4
26.2
26
Controls Patients
Group
Non-significant (p<0.05)
Volume of CST in the internal capsule is
larger in patients than controls
51
50
49
48
Volume
47
46
45
44
43
Controls Patients
Group
Non-significant (p<0.05)
Pending…
• Does disease severity correlate with FA
and ability to track between internal
capsule and Primary motor cortex?
• Does diagnosis correlate with either of
these points?