Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis.
ABSTRACT While the hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract in combination with lower motor neuron degeneration, the clinical involvement of both compartments is characteristically variable and the site of onset debated. We sought to establish whether there is a consistent signature of cerebral white matter abnormalities in heterogeneous ALS cases.
In this observational study, diffusion tensor imaging was applied in a whole-brain analysis of 24 heterogeneous patients with ALS and well-matched healthy controls. Tract-based spatial statistics were used, with optimized voxel-based morphometry of T1 images to determine any associated gray matter involvement.
A consistent reduction in fractional anisotropy was demonstrated in the corpus callosum of the ALS group, extending rostrally and bilaterally to the region of the primary motor cortices, independent of the degree of clinical upper motor neuron involvement. Matched regional radial diffusivity increase supported the concept of anterograde degeneration of callosal fibers observed pathologically. Gray matter reductions were observed bilaterally in primary motor and supplementary motor regions, and also in the anterior cingulate and temporal lobe regions. A post hoc group comparison model incorporating significant values for fractional anisotropy, radial diffusivity, and gray matter was 92% sensitive, 88% specific, with an accuracy of 90%.
Callosal involvement is a consistent feature of ALS, independent of clinical upper motor neuron involvement, and may reflect independent bilateral cortical involvement or interhemispheric spread of pathology. The predominantly rostral corticospinal tract involvement further supports the concept of independent cortical degeneration even in those patients with ALS with predominantly lower motor neuron involvement clinically.
- SourceAvailable from: ncbi.nlm.nih.govJournal of Neurology Neurosurgery & Psychiatry 11/1960; 23(4):269-82. · 4.92 Impact Factor
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ABSTRACT: It is proposed that the primary cell involved in amyotrophic lateral sclerosis (ALS) is the corticomotoneuron. The spinal motoneuron becomes affected as a result of antegrade effects. This hypothesis does not negate most of the presently popular theories regarding the pathogenesis of ALS, but directs focus to one cell type--the corticomotoneuron. It takes cognizance of the complex, monosynaptic, corticomotoneuronal-spinomotoneuronal connections that have evolved in primates, and especially in man. It might explain the lack of any natural or thus far induced animal model which closely mimics the human disease. Threshold measurements to transcotical magnetic stimulation might be used to test the hypothesis. Replication of ALS in an animal is only likely to succeed in a nonhuman primate.Muscle & Nerve 03/1992; 15(2):219-24. · 2.31 Impact Factor
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ABSTRACT: Aim of present study was to evaluate changes in diffusion tensor imaging (DTI) parameters in the whole brain of 28 patients with amyotrophic lateral sclerosis (ALS) compared to 26 healthy controls. In both fibertracking and voxel-based analysis, quantitative comparisons of the diffusion parameters between ALS patients and controls were performed. Correlation analyses of diffusion parameters and disease duration and disease severity were performed. A second DTI examination was acquired, allowing the evaluation of the effect of disease progression on the diffusion parameters. Fibertracking analysis revealed that especially the precentral part of the corticospinal tract (CST) was impaired. In the voxel-based analysis, it was shown that changes of diffusion parameters occurred throughout the brain, including frontal, temporal and parietal lobes. Disease severity was inversely correlated with the fractional anisotropy (FA). In the follow-up examination, a further decline of FA over time could be demonstrated in the CST as well as in the whole brain white matter. This study provides support for the view of ALS as being a multisystem degenerative disease, in which abnormalities of extra-motor areas play an important role in the in vivo physiopathology.NeuroImage 02/2007; 34(2):486-99. · 6.25 Impact Factor
Corpus callosum involvement is a
consistent feature of amyotrophic
N. Filippini, PhD*
G. Douaud, PhD*
C.E. Mackay, PhD
S. Knight, BSc
K. Talbot, DPhil
M.R. Turner, PhD
Objective: While the hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract in combi-
nation with lower motor neuron degeneration, the clinical involvement of both compartments is
characteristically variable and the site of onset debated. We sought to establish whether there is
a consistent signature of cerebral white matter abnormalities in heterogeneous ALS cases.
Methods: In this observational study, diffusion tensor imaging was applied in a whole-brain analy-
sis of 24 heterogeneous patients with ALS and well-matched healthy controls. Tract-based spa-
tial statistics were used, with optimized voxel-based morphometry of T1 images to determine any
associated gray matter involvement.
Results: A consistent reduction in fractional anisotropy was demonstrated in the corpus callosum
of the ALS group, extending rostrally and bilaterally to the region of the primary motor cortices,
independent of the degree of clinical upper motor neuron involvement. Matched regional radial
diffusivity increase supported the concept of anterograde degeneration of callosal fibers ob-
served pathologically. Gray matter reductions were observed bilaterally in primary motor and
supplementary motor regions, and also in the anterior cingulate and temporal lobe regions. A post
hoc group comparison model incorporating significant values for fractional anisotropy, radial dif-
fusivity, and gray matter was 92% sensitive, 88% specific, with an accuracy of 90%.
Conclusion: Callosal involvement is a consistent feature of ALS, independent of clinical upper
motor neuron involvement, and may reflect independent bilateral cortical involvement or inter-
hemispheric spread of pathology. The predominantly rostral corticospinal tract involvement fur-
ther supports the concept of independent cortical degeneration even in those patients with ALS
with predominantly lower motor neuron involvement clinically. Neurology®2010;75:1645–1652
ALS ? amyotrophic lateral sclerosis; ALSFRS-R ? revised Amyotrophic Lateral Sclerosis Functional Rating Scale; CC ?
corpus callosum; CST ? corticospinal tract; DD ? disease duration; DTI ? diffusion tensor imaging; FA ? fractional anisot-
ropy; FTD ? frontotemporal dementia; GM ? gray matter; LMN ? lower motor neuron; MD ? mean diffusivity; PLS ? primary
lateral sclerosis; PMA ? progressive muscular atrophy; RD ? radial diffusivity; UMN ? upper motor neuron; WM ? white
A major issue in amyotrophic lateral sclerosis (ALS) is phenotypic heterogeneity. While ALS is
characterized by simultaneous upper motor neuron (UMN) and lower motor neuron (LMN)
degeneration, phenotypes are recognized in which degeneration in one or more compartments
appears dominant, termed progressive muscular atrophy (PMA) where there is LMN-only
involvement clinically and primary lateral sclerosis (PLS) where involvement is UMN only.
The nature of this observed spectrum of compartmentalization of motor neuron pathology is
not understood, and extremes can present a diagnostic challenge early in the disease course.
*These authors contributed equally to this work.
From the University of Oxford Centre for Functional Magnetic Resonance of the Brain (FMRIB) (N.F., G.D., C.E.M., M.R.T.), University of
Oxford Centre for Clinical Magnetic Resonance Research (OCMR) (N.F., C.E.M., S.K., M.R.T.), and University of Oxford Department of Clinical
Neurology (K.T., M.R.T.), John Radcliffe Hospital, Oxford; and University of Oxford Department of Psychiatry (N.F., C.E.M.), Warneford
Hospital, Oxford, UK.
Study funding: The Oxford Motor Neuron Disease Care & Research Centre receives funding from the Motor Neurone Disease Association UK Care
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Martin
Turner, Department of Clinical
Neurology, West Wing Level 3,
John Radcliffe Hospital, Oxford,
OX3 9DU, UK
Copyright © 2010 by AAN Enterprises, Inc.
The disappointing progress in therapeutic
trials in ALS, despite advances in the under-
standing of pathogenesis,1has been partly at-
tributed to a lack of biomarkers, although
there are emerging candidates.2A particular
challenge for any biomarker is that it must
hold true across a range of phenotypes, and,
in addition to diagnostic and therapeutic
monitoring value, resolving issues about the
onset and spread of pathology in ALS may
also be important in identifying the at-risk
Diffusion tensor imaging (DTI) is now es-
tablished as a robust noninvasive MRI tool to
perform in vivo neuropathologic study of
white matter (WM) neuronal tracts.3We
studied a group of heterogeneous patients
with ALS of variable UMN involvement clin-
ically using DTI at 3 Tesla to achieve high
spatial and angular resolution. Analysis of the
entire brain was used to detect common re-
gions of WM damage that might inform con-
cepts of focality and spread. Associated gray
matter (GM) volumetric changes were ex-
plored using an optimized voxel-based mor-
METHODS Participants. Consecutively consenting pa-
tients with sporadic ALS were recruited from the Oxford Motor
Neuron Disease Care & Research Centre as part of the Oxford
Study for Biomarkers in Motor Neuron Disease (BioMOx,
www.biomox.net). All patients were initially diagnosed by 1 of 2
experienced ALS neurologists (K.T., M.R.T.) according to re-
vised El Escorial criteria. Two patients with PLS and PMA (i.e.,
no detectable LMN or UMN signs, respectively, at the time of
scanning), were excluded from the current analysis presented as
there were insufficient numbers to permit meaningful direct
comparison with the larger ALS group, given that their inclusion
within the same spectrum is still debated.
Twenty-four closely age- and gender-matched healthy con-
trols were recruited for comparison.
ALS clinical and functional measures. All patients under-
went clinical examination and El Escorial classification on the
day of study (M.R.T.). Patients’ functional status was measured
using the revised Amyotrophic Lateral Sclerosis Functional Rat-
ing Scale (ALSFRS-R). A quantitative assessment of clinical
UMN involvement was based on a scale used in a previous ALS
neuroimaging study.4This UMN score was based upon the
number of pathologic reflexes (recorded by M.R.T. in advance of
the scan), elicited from 15 body sites: glabellum, orbicularis oris,
masseter (jaw jerk), biceps, triceps and finger jerks bilaterally,
and knee, ankle, and Babinksi responses bilaterally. Disease du-
ration (DD) was calculated from symptom onset to scan date in
months. In view of the central hypothesis concerning a focal
cortical onset to the disease, prior to analysis patients with ALS
were classified by the presumed dominant hemisphere for disease
onset, defined as the contralateral hemisphere to the initial later-
ality of limb symptoms reported.
Standard protocol approvals, registrations, and patient
consents. Ethical approval for all procedures was obtained
prior to study (08/H0605/85 and 07/K1604/43). Written in-
formed consent was obtained from all participants.
Image acquisition. Scans were performed at the Oxford Cen-
tre for Clinical Magnetic Resonance Research using a 3-T Sie-
mens Trio scanner (Siemens AG, Erlangen, Germany) with a
12-channel head coil. Whole-brain diffusion-weighted imaging
was performed using a spin echo sequence (repetition time/echo
time ? 9,300/94 msec, field of view 192 mm, 2 mm isotropic
resolution, b value ? 1,000 s/mm2, 60 isotropically distributed
gradients). High-resolution 3-dimensional T1-weighted MRI
scans were acquired using a magnetization-prepared rapid gradi-
ent echo sequence (repetition time/echo time ? 2,040/4.7 msec,
flip angle 8°, field of view 192 mm, 1 mm isotropic resolution).
Image analysis and statistics. Detailed methods are provided
online (e-Methods on the Neurology®Web site at www.neurology.
org). In summary, whole-brain analysis of fractional anisotropy
(FA), mean diffusivity (MD), radial diffusivity (RD), and axial dif-
fusivity maps was carried out using tract-based spatial statistics.
Group comparison and correlation with UMN scores, ALSFRS-R,
and DD within the patient group were carried out using
permutation-based nonparametric inference within the framework
of the general linear model. An optimized voxel-based morphome-
try approach was used to identify any group-related differences in
analyses between diffusion and GM values extracted for each sub-
ject, using a mask of the significant group-related differences, were
sensitivity, specificity, and accuracy values to distinguish heteroge-
neous ALS from controls, using a model comprising significant
overlapping group-related differences for all diffusion indices and
significant GM results.
RESULTS Participants. Twenty-four consecutively
enrolled patients with ALS underwent MRI with
closely age- and gender-matched healthy control sub-
jects (table 1).
The breakdown of patients by revised El Escorial
criteria clinically was definite (n ? 7), probable/
probable laboratory-supported (n ? 9), and possible
(n ? 8). First limb of involvement was right-sided in
14 and left-sided in 9, plus 1 patient with progressive
bulbar palsy without clinical limb involvement to
date. Analysis of the data without image rotation ac-
cording to laterality did not materially alter the re-
sults reported, neither did the exploratory inclusion
of the 2 excluded patients with PLS and PMA, re-
spectively, though the latter will be the subject of
future dedicated group comparison.
Whole-brain group differences in FA replicated earlier
postmortem study. FA was reduced in the ALS pa-
tient group compared to healthy controls within the
corpus callosum (CC) and bilaterally in WM tracts
known to extend from the central CC to primary
motor and premotor cortex, including parts of the ros-
Neurology 75November 2, 2010
ditional, weaker regional differences were observed
caudally in the CST, including brainstem (p ? 0.05
uncorrected). All changes, notably including the CC,
were strikingly similar to those documented in a previ-
ously published postmortem pathologic study5(figure
1). Whole-brain FA (and GM) reductions were not in-
fluenced by the inclusion of DD as a nuisance covariate
in the analysis (figure e-1).
Whole-brain FA correlated with UMN score in the
CST but not CC in patients with ALS. Within the
patient group, significant voxel-wise correlations be-
tween FA and clinical measures were observed. For
reduced FA vs increased UMN score, correlation was
seen bilaterally in the CST (p ? 0.05 corrected), but
not in the CC. For reduced FA vs lower ALSFRS-R,
a weaker correlation (p ? 0.05 uncorrected) was
found in several regions, including parts of the CC.
Correlation between increased FA and longer DD
also localized bilaterally to the CST (p ? 0.05 cor-
rected; figure e-2).
Whole-brain group differences in RD overlapped with
FA differences. Increased RD values were observed in
patients with ALS compared with controls in the CC
and bilaterally in the WM connecting primary and
premotor cortex (p ? 0.05 corrected). These regions
colocalized with FA reductions (figure 2). No signif-
icant group differences were found in mean or axial
Whole-brain GM volumetric group differences showed
spatial correspondence to FA change. Analysis of GM
volumetric differences between patients with ALS and
controls revealed widespread areas of reduction includ-
ces, cingulate cortex, and temporal lobe regions. There
was good anatomic correspondence between motor-
related GM atrophy and DTI-derived (FA, RD)
changes (figure 3). Regional volume changes were
bilateral despite our standardization for laterality of
Figure 1Regional fractional anisotropy (FA) reductions in amyotrophic lateral sclerosis group whole-brain comparison with healthy
controls, alongside published postmortem observations
Consistent corpus callosum (CC) and rostral corticospinal tract (CST) tract involvement was seen despite the inclusion of a large number of patients with
few clinical upper motor neuron signs. Similar white matter tract degeneration sections alongside those taken from an historical pathologic study5(left-
side images of A–D) confirmed prominent involvement of the CC and rostral CST (A and B, thick black lines indicating primary motor cortex), with caudal
CST changes seen in uncorrected FA results (A, C, and D). Images shown were corrected (red–yellow scale) and uncorrected (red-only scale) for multiple
comparisons (p ? 0.05; radiologic convention used for display in all images).
Table 1 Participant characteristics
Age, y, mean ? SD (range)
59 ? 12 (34–78) 58 ? 12 (31–83)
Handedness for writing, R:L
Disease duration, mo, mean ? SD (range)
NA48.7 ? 38.2 (10–122)
Age at onset, y, mean ? SD (range)
NA 54.7 ? 11.6 (30–74)
UMN score, mean ? SD (range)
NA8.6 ? 4.2 (1–15)
ALSFRS-R, mean ? SD (range)
NA33.1 ? 3.6 (26–39)
Abbreviations: ALS ? amyotrophic lateral sclerosis; ALSFRS-R ? revised Amyotrophic Lat-
eral Sclerosis Functional Rating Scale; UMN ? upper motor neuron.
Neurology 75November 2, 2010
limb onset, and in the uncorrected data (not shown)
there was bilateral temporal lobe involvement, sug-
gesting that apparent lateralization in this area was a
Combining measures. Further post hoc investigation
showed that both group-related differences in FA
and RD were highly correlated with GM differences
across subjects (FA and GM: ? ? 0.64, p ? 10?4;
RD and GM: ? ? ?0.61, p ? 10?4; figure 4).
Discriminant analysis using the combination of
all 3 measures improved the classification of the sub-
jects into 2 groups with 92% sensitivity, 88% speci-
ficity, and 90% accuracy, performing better than
discriminant analyses based on each one of these
measures considered separately (table e-1).
DISCUSSION This study demonstrated a consistent
involvement of the CC and rostral CST across a het-
erogeneous group of patients with ALS, including
those with little clinical UMN involvement, support-
ing the concept of an independent cerebral patho-
genic process in ALS. While CC involvement might
relate to interhemispheric spread, it might equally
reflect secondary damage due to independent bilat-
eral cortical processes. Multimodal MRI has the po-
tential to discriminate heterogeneous ALS from
controls, and can generate noninvasive biomarkers.
DTI is sensitive to the motion of water molecules.
Tightly confined water movement in intact neuronal
pathways will be anisotropic (i.e., strongly direc-
tional, along the main direction of the fibers),
whereas damaged pathways will result in less re-
stricted movement of water in multiple directions
leading to a reduction in anisotropy. The application
of DTI to ALS has been refined over a decade from
the initial experience,6with CST and more wide-
spread WM changes reported to varying degrees.2
Such studies have generally involved more homoge-
neous patients with ALS with UMN signs in 2 or
more body territories.
Our assessment of UMN involvement was based on
reflexes. The localization of FA and UMN score corre-
lations to the CSTs supports our view that pathologic
reflexes at the bedside accurately reflect pathology in
this neuronal compartment in a quantitative way. Sev-
eral targeted DTI studies in ALS have also reported a
relationship between clinical UMN involvement and
CST FA,7-9or brainstem FA10reductions.
A debate over spinal anterior horn retrograde11vs
anterograde corticomotoneuronal degeneration12
Figure 2 Regional fractional anisotropy (FA) reductions and radial diffusivity (RD) increases in amyotrophic
lateral sclerosis (ALS) group whole-brain comparison with healthy controls
The close overlap between FA reductions (top panel, red–yellow) and RD (lower panel, blue) findings suggests that involve-
ment of the corpus callosum and rostral corticospinal tract in ALS reflects a secondary demyelinating process due to an
anterograde Wallerian degeneration. Both measures were corrected for multiple comparisons (p ? 0.05; radiologic conven-
tion used for display in all cases with sagittal sections specifically marked for side).
Neurology 75November 2, 2010
continues, though the 2 concepts are not mutually
exclusive. Clinicopathologic studies support a corti-
cal as well as spinal focus.13The whole-brain FA re-
ductions found in our study were most marked in the
rostral CST, despite a broad range of UMN involve-
ment clinically in our participants, including nearly
one-third of patients categorized as only possible
ALS as a result of few UMN signs. This rostral em-
phasis has been observed before14and supports an
active cortical process, rather than UMN involve-
ment occurring solely due to dying back from a focal
onset of pathology in the anterior horn of the cord.
A within-group positive correlation was found be-
tween DD and CST FA. A potential confound was
the negative correlation noted between DD and
UMN scores in our patient group (? ? ?0.61, p ?
0.002). More speculatively the CST may be more
resistant to disease-related damage in some patients
with ALS or such individuals have a higher baseline
FA, either way then reflected in a longer disease
course. Given that post hoc analysis showed that the
effect in FA was largely due to a reduction in RD, we
speculate that longevity might reflect more myelin-
ated or higher packing density of axons in this path-
way. Longitudinal DTI studies in ALS are needed to
confirm the true nature of these observations, but
have been scarce due to the practical challenge of
MRI in those for whom there is rapid progression
and disability. One study has demonstrated progres-
sive FA decreases in the CST.15
Postmortem study specifically noted CC degener-
ation to be prominent in ALS,5and there was a strik-
ing similarity in the distribution of the degenerating
fibers when compared with our study (see figure 1).
Several DTI studies have also reported variable de-
grees of FA change within the CC as part of a wider
array of cerebral WM changes in ALS.14,16,17Changes
in MD reported within parts of the CC14,18were not
detected in our study.
Diffusion tensor tractography can been used to
parcellate regions according to their wider cortical
connectivity.19This confirms that the fibers of the
mid-body of the CC, where we found the strongest
group-related differences in FA, appear largely to link
to the motor and premotor cortices. This central por-
tion of the CC was also noted to be most markedly
involved in postmortem pathologic study.5In a pre-
vious ALS study employing tract-based spatial sta-
Figure 3 Gray matter (GM) and fractional anisotropy (FA) reductions in amyotrophic lateral sclerosis (ALS)
group whole-brain comparison with healthy controls
lobes were found, many with close relation to the regional white matter changes revealed by FA reductions (red–yellow).
Motor region–related GM involvement was bilateral despite correction for laterality of limb onset, with the possibility that
the corpus callosum involvement reflects independent bilateral cortical processes, or interhemispheric spread of pathol-
ogy in ALS. Images were corrected for multiple comparisons (p ? 0.05; radiologic convention used for display in all cases
with sagittal sections specifically marked for side).
Neurology 75 November 2, 2010