Spinal cord markers in ALS – Diagnostic
and biomarker considerations
REVIEW ARTICLE
Peter Bede, Arun L. W. Bokde, Susan Byrne, Marwa Elamin, Andrew J Fagan, Orla Hardiman
Trinity College Institute of Neuroscience, Dublin, Ireland
Centre for Advanced Medical Imaging (CAMI), St. James’s Hospital / Trinity College Dublin, Ireland
ABSTRACT
Background: Despite considerable involvement of the spinal cord in Amyotrophic Lateral Sclerosis
(ALS), current biomarker research is primarily centred on brain imaging and CSF proteomics. In
clinical practice, spinal cord imaging in ALS is performed primarily to rule out alternative conditions
in the diagnostic phase of the disease. Quantitative spinal cord imaging has traditionally been
regarded as challenging, as it requires high spatial resolution while minimizing partial volume effects,
physiological motion and susceptibility distortions. In recent years however, as acquisition and post
processing methods have been perfected, a number of exciting and promising quantitative spinal
imaging and electrophysiology techniques have been developed.
Methods: We have performed a systematic review of the trends, methodologies, limitations and
conclusions of recent spinal cord studies in ALS to explore the diagnostic and prognostic potential of
spinal markers.
Results: Novel corrective techniques for quantitative spinal cord imaging are systematically
reviewed. Recent findings demonstrate that imaging techniques previously used in brain imaging,
such as diffusion tensor, functional and metabolic imaging can now be successfully applied to the
human spinal cord. Optimized electrophysiological approaches make the non-invasive assessment of
corticospinal pathways possible, and multimodal spinal techniques are likely to increase the
specificity and sensitivity of proposed spinal markers.
Conclusions: Spinal cord imaging is an emerging area of ALS biomarker research. Novel quantitative
spinal modalities have already been successfully used in ALS animal models and have the potential
for development into sensitive ALS biomarkers in humans.
INTRODUCTION
Biomarker research in Amyotrophic Lateral Sclerosis (ALS) is an active field of neurological research.
Although no single such marker has been validated to date, serum1, CSF, electrophysiological and
neuroimaging2 based markers are currently undergoing extensive investigation3.
Because of the significant disease heterogeneity, sufficient patient numbers are required to
augment statistical power. Structured international collaborations are now underway to share high
quality multicentre imaging data in ALS.4 In recent years novel quantitative MRI techniques, fast
acquisition times and effective artefact correction methods have led to better clinical correlation
and increased utility in spinal imaging in ALS both in humans and in animal models. However, despite
these significant advances, no systematic analysis of spinal cord studies in ALS can be identified.
Notwithstanding, the sensitivity of advanced spinal cord imaging techniques such as diffusion tensor
imaging have been successfully demonstrated in several neurological conditions such as multiple
sclerosis5 , spinal cord compression6, cord injury7, spinal artery occlusion8, spinal tumours 9,
syringiomyelia10, inflammation11 and arteriovenous malformations12.
In addition to cross sectional spinal cord imaging studies, longitudinal studies have been published
both in multiple sclerosis (MS)5 and ALS13 and spinal imaging has been used to assess medication
effect in multiple sclerosis14.
SEARCH STRATEGY AND SELECTION CRITERIA
Publications were searched during a 4 month period between May 2011 and August 2011. Only
articles published in English were reviewed. Further articles were identified through reviews of the
references of these articles. Reports from meetings were also used if they presented relevant
information.
The literature search was performed using Pub Med with the following keywords: Motor Neuron
Disease (MND), Amyotrophic Lateral Sclerosis (ALS), Biomarker, Marker, Spinal cord, Diffusion tensor
imaging, Magnetic resonance spectroscopy, Voxel based morphometry, Longitudinal, Crosssectional, Upper motor neuron, Atrophy, Electrophysiology, Transcranial magnetic stimulation, ALS
Animal Model, SOD1 Mice. The keywords Motor Neuron Disease (MND) and Amyotrophic Lateral
Sclerosis (ALS) were separately combined with each of the other keywords as pairs of keywords.
RESULTS
Spinal markers in ALS Animal models
Magnetic Resonance Microscopy (MRM) of ALS animal models can achieve 41 µm isotropic
resolution on brain and 35 µm isotropic resolution on spinal cord imaging15. Such high spatial
resolution is comparable with traditional histological techniques without the tissue distorting effects
of fixation, sectioning and staining.
The sensitivity of spinal DTI in SOD1 mouse model of ALS has been elegantly demonstrated
recently16 opening the opportunity for measuring therapeutic response in animal models.
Magnetic resonance spectroscopy (MRS) has also been applied to FALS mice spinal cord17 showing
decreased N-acetyl aspartate (NAA), N-acetylaspartylglutamate (NAAG) as well as increased
glutamate, taurine and inositol levels. Interestingly, in SOD1 mice the metabolic abnormalities are
most pronounced in the spinal cord, followed by medulla and then the sensorimotor cortex. This
observation may provide further rationale for the development and validation of spinal markers.
Pharmacologic MRI (phMRI) has been successfully used in a rat model of familial ALS18 in which
response to amphetamine was assessed, demonstrating upregulation of pre-motor areas and
impaired activation of the primary motor cortex. These changes reflect results of traditional motor
task fMRI studies. This brain study indicates how innovative pharmacological approaches can be
applied to ALS imaging, and has the potential to open the way for future spinal applications.
Spinal markers in ALS – Human applications
Conventional MRI techniques
High signal changes along the corticospinal tracts (CST) in the brain on fluid attenuated inversion
recovery (FLAIR), T1 and T2 weighted imaging have been long described in the literature, but have
been shown to be poorly sensitive19 and specific for ALS20 21.
CST signs are also well described on spinal imaging22, but their significance is uncertain. Terao et al.23
reported that 9 out 13 patients had spinal CST signs. Thorpe et al.24 reported that axial imaging
revealed high signal in the lateral white matter in eight out of eleven patients. They highlight that
two of their patients had only cord hyperintensities without brain signs, suggesting that spinal cord
MRI may increase the sensitivity of detecting radiological signs of corticospinal pathway pathology.
However, such signs are unlikely to be useful for diagnostic or biomarker purposes.
Simple measures of spinal cord atrophy such as spinal cord cross-sectional area (SCCA) have been
successfully correlated with clinical function in Multiple Sclerosis (MS)25 and in chronic incomplete
spinal cord injury (SCI)26. Objective volumetric techniques used in brain imaging such as 3D-modified
driven equilibrium Fourier transform (3D-MDEFT) based acquisition protocols have also been shown
to quantify spinal cord cross-sectional areas reliably27. Spinal cord atrophy was originally considered
to be a possible feature of ALS, and Agosta et al. found that cross-sectional area decreases over time
on longitudinal spinal cord imaging in ALS.13 However, the specific methods by which cross sectional
axial spinal cord areas are quantified vary considerably, and other imaging studies have failed to
confirm this28.
Diffusion Tensor Imaging (DTI)
Various studies use different DTI parameters such as Fractional Anisotropy (FA), Mean Diffusivity
(MD), Radial Diffusivity (RD), or Axial Diffusivity (AD) and have selected different spinal segments as
their region of interest (ROI). Many studies have attempted clinical correlation with the intention of
validating the sensitivity of their imaging methods.
Valsasina et al.29 conducted a study of 28 ALS patients and 20 healthy controls. They demonstrated
that patients with ALS had significantly lower average fractional anisotropy of the cervical cord and
found significant correlation between cord average fractional anisotropy and ALSFRS.
In a longitudinal spinal MRI study Agosta et al.30 demonstrated a significant decrease in cord average
FA and a significant increase in cord average mean diffusivity (MD) in patients with ALS during a
mean follow-up of 9 months.
The majority of the studies have been of the superior cervical cord. Nair et al. conducted a
multisegmental cervical spinal cord DTI study31 and concluded that FA and RD differences between
healthy subjects and ALS patients are greater in the more distal segments of the cervical cord.
A number of novel diffusion-weighted imaging techniques have been developed that are ideally
suited to spinal applications and may be superior to standard DTI. Q-ball imaging (QBI) is a high
angular resolution diffusion imaging (HARDI) method that allows the detection of crossing fibres. QBI
offers significant additional benefit to conventional DTI by retrieving commissural, medio-lateral and
dorso-ventral fibres in the spinal cord as well as the longitudinal fibres easily recovered by DTI32.
Contiguous-slice zonally orthogonal multislice (CO-ZOOM-EPI)33 is another new technique that
provides high resolution with reduced susceptibility distortions, making it an attractive spinal
imaging method.
Similarly to brain studies, the usefulness and sensitivity of multi-parametric MRI has been
demonstrated in the human spinal cord by Cohen-Adad et al34 , by combining high angular resolution
diffusion imaging (HARDI), magnetization transfer(MT) and measures of cord atrophy, showing
degeneration in normal appearing human spinal cord with good clinical correlation.
Magnetic resonance spectroscopy (MRS)
Magnetic resonance spectroscopy allows the non invasive measurement of different metabolites in
a predefined voxel. The most frequently used metabolites include N-acetyl aspartate(NAA),
Choline(Cho), Creatine(Cre), Myo-inositol(Myo), and Lactate. High absolute or relative (NAA/Cho,
NAA/Cre+Cho) N-acetyl aspartate levels are considered to be a marker of neural integrity. Creatine
levels are regarded as a marker for metabolic activity, and choline a marker of membrane integrity.
MRS studies can define their region of interest (ROI) in a single voxel – as if taking a virtual biopsy or can use a grid of multiple volumes in multi-voxel techniques.
In the brain, MRS has been extensively used in ALS, in cross sectional, longitudinal35, medication
effect36 37, motor cortex38, brain stem39 40, extra-motor cortex41, single voxel42 and multivoxel
studies. The technique is generally regarded as a sensitive non invasive modality to identify and
follow up early metabolite abnormalities in ALS. The validation of brain MRS studies in ALS is based
on clinico-pathological correlations.
Despite the potential advantages of spinal cord MRS, such as measurement of medication effects
and the inclusion of the anterior horns, very few successful spinal cord MRS studies can be identified
in the literature. The technical challenges include relatively small volumes, small signal to noise ratio,
longer imaging times and strong magnetic field inhomogeneities in the relevant regions.
A series of corrective imaging techniques, such as ECG triggering and higher-order shimming have
been proposed to perform successful MRS in the cervical spinal region.43 A single voxel cervical
spinal MRS study44 found that NAA/Myo and NAA/Cho correlated with the forced vital capacity
(FVC).
One of the most interesting additions to the ALS spectroscopy literature is a cervical spinal cord
study of non-symptomatic people with SOD1 gene mutation. Carew et al.45 found reduced
neurometabolite radios in SOD1+ individuals compared to SOD1- healthy controls in advance of
onset of symptoms. The predictive value of abnormal MRS in SOD1+ individuals in forecasting
symptom onset is likely to be clarified by longitudinal studies. This study raises very important
questions on presymptomatic biomarker development for asymptomatic people with known fALS
mutations.
Spinal functional MRI (fMRI)
Functional brain MRI (fMRI) is used extensively in ALS research. Approaches include motor
paradigms46, experimental neuropsychology tasks47 48 and resting state protocols49. Despite
technical difficulties (Table 1.) a number of spinal cord fMRI studies have now been carried out both
in animal models50 and humans51.
Spinal fMRI challenges
Correction techniques
Small cross-sectional dimensions of
the spinal cord require high
resolution imaging to distinguish
between gray and white matter and
to avoid partial volume effects,
however small voxels provide poor
signal-to-noise ratio
Multiple methods have been developed:
Magnetic field inhomogeneities
caused by spinal cord / vertebral
body interface
spin-echo imaging techniques with short echo times
Motion artifacts due to
cerebrospinal fluid, blood flow,
respiration
Cardiac and respiratory gating
1., transverse / axial slices with high in-plane resolution
<2mm, with relatively large slice thickness ~10mm
2., Thin slice sagittal acquisition, followed by 3D volume
reformatting and corrected by smoothing in the rostralcaudal direction52
Using SEEP (signal enhancement by extravascular water
protons) contrast (Stroman et al. 2001)
Breath-hold acquisition
Flow compensation gradients
Spatial saturation pulses
Retrospective image correction techniques based on cardiorespiratory physiological noise models (Brooks et al.53)( Figley
et al54)
Independent component analysis (ICA) to identify cardiac
components in spinal fMRI data (Piche et al)55
Poor spatial distribution of
activation and reproducibility
gradient echo echo-planar imaging (GE-EPI) is superior to
turbo spin echo (TSE) spinal fMRI56
Table 1. Technical challenges of spinal functional MRI
Early human spinal fMRI studies were primarily based on sensory stimulation, demonstrating dorsal
horn activation in the relevant cord segments57. Motor task based human spinal fMRI studies have
been successfully carried out in healthy individuals both with upper58 59 and lower limb tasks60.
Clinical applications of spinal fMRI techniques include Multiple Sclerosis (MS)61, spinal cord injury62
and pain medicine. While no spinal fMRI study has been published in ALS to date, this technique
might be particularly applicable to ALS research. Activity of brain stem cranial nerve nuclei can be
visualised with fMRI63, making it a potentially attractive method in bulbar ALS patients. Spinal cord
fMRI could also be investigated and validated as a potential non invasive marker in ALS.
Current clinical applications
In current clinical practice spinal MRI is only performed in selected atypical cases to exclude possible
alternative diagnosis64 (Table 2). However, recent innovations have addressed many of the technical
limitations of spinal imaging (Table 3) and the superior cervical spinal cord can now be successfully
scanned in humans without significant motion artifacts. The main ALS specific MRI challenges
include dyspnoea, orthopnoea, sialorrhea and impaired communication between the radiographer
and patients with bulbar involvement.
Hirayama disease65
Space occupying lesions; Spinal tumours, abscesses or haematomas
Degenerative changes; cervical or lumbar radiculomyelopathy (spondylosis)
Syringomylelia
Anterior spinal cysts (Extra- or intradural)66
Transverse myelitis
Supeficial Sideoris 67
Table 2. Possible ALS mimics requiring spinal MRI for exclusion
Source of imaging artifacts in spinal imaging
Techniques for Corrections
CSF flow
Quick acquisition protocols
Small axial cross sectional area, partial
volume errors (PVE)
High field scanners, high resolution, axial acquisitions
Low Signal to Noise Ratio in DTI sequences
Decreasing EPI factor, fast single-shot EPI with use of
sensitivitiy encoding (SENSE)68 , multishot echoplanar imaging69
Cardiac, arterial pulsation
Cardiac gating
Respiratory effects
Pulseoxymetric triggering, Quick acquisition, superior
cervical imaging
Swallowing effects, especially in patients
with sialorrhea
Rest slab or Saturation band placement to cover
pharyngeal regions anterior to the spinal cord,
Quick acquisition, superior cervical imaging
Parallel imaging technique using arrays of multiple
receiver coils70
Susceptibility artifacts and image distortion,
Problematic regions: skull base, the spinal
cord and the surrounding bony vertebral
column
Shimming over the region, using smaller EPI factor,
using thin slices, or short TE
Table 3. Technical challenges of spinal imaging
Pathological considerations
Although the spinal cord is heavily involved in ALS pathology and lower motor neuron involvement is
a diagnostic requirement in ALS, the majority of MRI biomarker research studies in ALS are brain
centred.
The “dying-back” 71 hypothesis is often used by imaging studies as an argument to study the spinal
cord in ALS. The concept of “Dying back” of axons towards the cell body is based on early
pathological observations72 that corticospinal tract degeneration in the spinal cord tends to be more
pronounced caudally than rostrally. In a detailed histological ALS case series Brownel et al.73
indicated that in 14 out of 35 cases pyramidal degeneration could not be traced above a certain
level. The ‘Dying back’ hypothesis was later supported by SOD1 animal models, where motor unit
loss was noted to precede motor neuron death. SOD1 mutant ALS mouse model studies74 suggest
that end-plate denervation takes place before there is evidence of ventral root or cell body loss, and
then ventral root axonal damage precedes motor neuron loss. However, mouse and human motor
systems show significant differences, so patterns of spread are best studied on human case series.
An elegant 3 dimensional model of disease spread was proposed by Ravits et al.75 based on focal
onset and the differing LMN and UMN somatotopic anatomy.
There is now emerging evidence that neuroimmune processes76 contribute to ALS pathology in the
brain77 and that significant microglia/macrophage activation also takes place in the spinal cord in
ALS78 79. This immune response provides a further biomarker target in the spinal cord, especially that
microglial activation in the spinal cord occurs early80, in the preclinical stage of ALS in SOD1 animal
models. Sites of microinflamation can be highlighted by magnetically labelled anti-CD4 antibodies a
technique called immune MRI (iMRI), a method that has already been successfully applied to ALS.81
Disruption of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) have been proposed
as important contributors to the microenvironment of ALS pathology82. BBB and BSCB permeability
can be assessed by dynamic contract-enhanced magnetic resonance imaging83 (DCE-MRI) using GdDTPA84 contrast or by the identification of hemosiderin deposition. Despite several human studies85,
most of the BBB and BSCB data in ALS is based on animal studies86 87. Recently, a high field 7 Tesla
brain imaging study in humans has shown no evidence of BBB disruption in ALS88, but the study was
confined to brain imaging. BBB and BSCB disruption in ALS offers another possible biomarker target
that has not been fully explored to date.
Electrophysiological markers
Transcranial magnetic stimulation (TMS)
Transcranial magnetic stimulation (TMS) was developed by Barker et al89 in 1985 and remains an
attractive area of research in ALS as it is relatively cheap, non-invasive, can detect early upper motor
neuron dysfunction and enables the assessment of both the cotriocosipnal and corticobulbar
pathways. Several TMS parameters have been developed and studied in ALS (Table 4).
1., A motor-evoked potential (MEP) is the compound muscle action potential produced in response
to a single transcranial magnetic stimulus
2., Central motor conduction time (CMCT): obtained by subtracting the peripheral conduction time
from the MEP latency
3., Corticomotor threshold
4., Cortical silent period duration
Table 4. Commonly used TMS parameters in ALS
Despite initial optimism regarding the diagnostic utility of TMS in ALS90, the practical application of
the technique remains controversial91. The published results on the sensitivity of TMS in identifying
UMN lesions in ALS are inconsistent. (Table 5) Central motor conduction time (CMCT) has been
consistently shown to be prolonged in ALS92 and by using a combination of different TMS
parameters, this sensitivity can be increased significantly93. Another technique, the triple stimulation
method, is has been reported to be of greater use in identifying early Upper Motor Neuron (UMN)
pathology in ALS94 95. F-wave studies have also been proposed as UMN markers96 in early stage ALS,
as a technique to identify subclinical UMN involvement in predominantly LMN dominant disease97.
Authors
Year of Patients
public with
ation
ALS(n)
Sensitivity of TMS
Remarks, Conclusion
Claus et al. 98
(CMCT)
1995
63
Abnormal CMCT
No significant longitudinal
recorded in 51% (n = 32) changes found on CMCT, poor
prognostic and predictive value
noted
Trompetto99
1998
30
Abnormal corticobulbar
TMS in 63.3%(n=19) ALS
patients
Masseter response to TMS was
found to be a sensitive way to
identify corticobulbar pathology
in ALS
Mills et al. 100
1998
65
Abnormal CMCT in 17%
(n=11) of patients
No correlation found between
CMCT and physical signs
Triggs et al.101
1999
121
TMS revealed UMN
dysfunction in 84 of 121
(69%) patients
TMS captured longitudinal
changes and also revealed UMN
dysfunction in 75% of patients
with only probable UMN signs.
Schulte–
Mattler102
1999
35
Abnormal CMCT in 67%
of patients with
probable UMN signs
and in 71% of patients
without UMN signs
No association with disease
duration or severity
Pouget et al.103
2000
54
Abnormal CMCT in 13
(24%) of 54 ALS patients
A shorter silent period was
identified as the most sensitive
TMS parameter in ALS, as it was
found to be abnormal in 38
(70%) of 54 ALS patients.
Urban et al.104
2001
51
Abnormal limb TMS in
54% (n=15) Abnormal
limb or bulbar TMS in
82% (n=23)
TMS was more sensitive in
identifying corticobulbar lesions
than cotricospinal involvement
in ALS
Desiato105
2002
25
Abnormal TMS in 96%
(n=24)of patients
Bulbar TMS was considered a
sensitive approach to identify
corticobulbar lesions in ALS
Kaufman et al.106
(CMCT)
2004
73
Abnormal TMS in 77 %
of patients
No significant relationship
found between abnormal TMS
and UMN signs
Table 5. A selection of large Transcranial magnetic stimulation (TMS) studies in ALS listed
chronologically and their sensitivity in detecting UMN pathology.
While state of the art electrophysiology techniques such as Motor Unit Number Estimation (MUNE)
and motor unit number index (MUNIX) were successfully developed into sensitive and pragmatic
LMN markers, after decades of TMS studies, TMS did not become a routine assessment tool in ALS
and the future of clinical UMN assessment seems unlikely to be TMS-based.
CONCLUSIONS
An ideal spinal ALS biomarker that has practical clinical and research applications must fulfil a
number of requirements (Table 6.) and proposed techniques should be assessed with these
requirements in mind. Despite significant advances in spinal imaging techniques, their limitations are
obvious from a biomarker perspective. While ALS specific pathology can be demonstrated on a
group level, it cannot be sensitively identified on a single subject level. Equally, available spinal
studies have neither captured segmental anterior horn cell pathology nor validated changes with
electrophysiological findings. Currently innovative spinal techniques remain aspirational in this
regard.
Practicality


Quick – well tolerated
Non - invasive

Cheap – cost effective

not only validated against healthy controls, but differentiating ALS from
other neurological conditions
Specificity
Sensitivity





Sensitive for diagnostic purposes
Predictive / Prognostic value
Role in assessment of response to therapy
Segregation of disease phenotypes
Correlation with disease severity; functional scores and other clinical
markers
Table 6. Requirements of an optimal biomarker in ALS
Common shortcomings of recent spinal cord studies in ALS (Table 7) are easy to identify, but
technical advances and focused international research collaborations are likely to correct for these
problems in the near future. Some of the current research based imaging techniques are expected
to “filter down” into every day clinical applications. Traditional clinical neuroimaging relies on the
subjective interpretation of imaging data by experienced radiologists and neurologists. This
approach is likely to be ill suited to the identification of subtle changes, such as volume loss in
neurodegeneration, especially in relatively rare conditions. It is likely that in the near future there
will be a paradigm shift from subjective image interpretation to quantitative imaging where data
acquired will be comparable to data banks of age, size and gender matched healthy and disease
controls.
Common Problems with spinal cord studies
Possible correction
Small patient numbers
International collaborations, multicentre studies
Poorly characterized participants, Lack of
well defined clinical measures
Prospective studies, Purpose designed clinical data
base, including symptom onset, UMN and LMN
measures
Lack of established UMN / LMN scores
Standardized clinical examination, Documentation of
LMN - electrophysiological findings, inclusion of
spasticity measures
Documentation of the total ALSFRS only and
not the limb, bulbar, respiratory functional
sub-scores. Usage of the total ALSFRS for
clinical correlation
In spinal studies, modification of the ALSFRS by
excluding the bulbar subscores, Acknowledgement of
the limitation of the ALSFRS as it relies heavily both
on LMN and UMN involvement.
Usage of limited DTI parameters (FA & MD)
Additional DTI parameters (RD, AD)
Studies using heterogeneous patient groups
with mixed ALS phenotypes
Well characterized patient groups with detailed
clinical profiling, Segregation of homogenous ALS
phenotypes
Comparison with healthy controls
Validation against other neurological disorders, MS,
Hirayama disease, stroke, MMN, spinal cord
infarction, spondylosis
Lack of pre-symptomatic longitudinal
imaging studies
Inclusion of presymptomatic individuals with
mutations in known fALS genes, such as SOD1 or
C9ORF72 hexanucleotide repeat expansion107 as a
separate study group.
Table 7. Common shortcomings of spinal cord imaging studies
Finally, short scanning time is crucial in ALS and related conditions. Multiparametric approaches are
likely to improve the sensitivity of spinal methods. DTI of the cervical cord, across the “well
organized” CSTs in the cervical cord can be acquired in a few minutes and is the most likely to be
developed into an UMN marker. The quick acquisition time of a DTI sequence makes it an ideal “add
on” to a structural cervical spinal MRI study that is frequently performed as part of the diagnostic
work-up, therefore eliminating the cost and discomfort of an additional scan. New generation highfield scanners, freely available high quality data processing software, effective post processing noise
reduction algorithms and quick scanning times make spinal imaging an attractive and promising area
of research in ALS. However, as is the case for brain studies, larger numbers and multicentre
international collaboration are required.
CONFLICTS OF INTEREST
There are no conflicts of interest.
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