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Review

Progress of magnetic resonance imaging in amyotrophic lateral sclerosis

Zhuozhi Dai a,b,c, Yanzhi Chen a,b, Gen Yan d, Gang xiao e, Zhiwei Shen a,b, Renhua Wu a,b,*
a
Department of Medical Imaging, The 2nd Affiliated Hospital, Medical College of Shantou University, Shantou, 515041, China
b
Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, T6G 2V2, Canada
c
Provincial Key Laboratory of Medical Molecular Imaging, Guangdong, Shantou 515041, China
d
Department of Radiology, Affiliated Hospital, Jiangnan University, Wuxi, China
e
Department of Mathematics and Information Technology, Hanshan Normal University, Chaozhou Guangdong 521041, China
Received 30 June 2018; revised 7 September 2018; accepted 30 November 2018
Available online ▪ ▪ ▪

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease with motor neuron disorder. Because the natural processes of ALS are
irreversible, early detection and early intervention are of great significance. However, there is lack of objective imaging indicator for the
diagnosis of ALS. The current diagnosis of ALS is primarily clinical, which make it difficult for early diagnosis especially when the clinical
symptoms are not obvious. As the exponential development of imaging technology, exploration and trials have been conducted continuously in
ALS. Therefore, a review is needed to find the possible imaging biologic markers to help ALS diagnosis. This article will comprehensively
analyze the application of traditional imaging and the latest imaging technology in ALS, especially the latest chemical exchange saturation
transfer research in ALS diagnosis conducted by our team. In addition, the prospects for the development of ALS diagnosis are forecasted.
© 2018 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Kewyords: Amyotrophic lateral sclerosis; Magnetic resonance imaging; Chemical exchange saturation transfer; Image biomarker

1. Introduction indicators for the assessment of ALS diagnoses [5]. The cur-
rent diagnosis of ALS is primarily clinical, which makes it
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal difficult for early diagnosis, especially when the clinical
disease and is a primarily motor neuron disorder. Current symptoms are not apparent [6].
evidence suggest that ALS is a multifactorial disease, while ALS is not only difficult to diagnose in its early stages, but
some studies indicate that it is related to neuro infection, with the current clinical assessment is also somewhat coarse and
a complex interaction with genetic and molecular pathways subjective [7]. Based on the EI Escorial criteria, the principle
[1e3]. Lesions to redox signal-transduction pathways in goal is to rule out other neurological diseases which have
mutant SOD1þ glial cells may stimulate broad-spectrum similar symptoms [8]. It is extremely important to get a detailed
upregulation of pro-inflammatory genes in ALS mouse history of symptoms observed by the professional physician
models [4]. Because the natural processes of ALS are irre- along with a series of tests. Electromyograms (EMG) and nerve
versible, early detection and early intervention are of great conduction studies (NCS) are two common ways to assess the
importance [1]. However, there are a lack of objective imaging electrical activity of the muscle fibers, which can help ALS
diagnosis. However, these means of assessing are not specific.
Moreover, the abnormalities in EMG and NCS may only sug-
* Corresponding author. Department of Medical Imaging, The 2nd Affiliated gest the peripheral neuropathy or myopathy, which cannot
Hospital, Medical College of Shantou University, Shantou 515041, China. reflect the situation in the brain in ALS [9].
E-mail address: [email protected] (R. Wu).
Peer review under responsibility of Beijing You'an Hospital affiliated to
To provide an objective indicator in the brain, magnetic
Capital Medical University. resonance imaging (MRI) may also be ordered by the physician

https://doi.org/10.1016/j.jrid.2018.11.002
2352-6211/© 2018 Beijing You’an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Dai Z et al., Progress of magnetic resonance imaging in amyotrophic lateral sclerosis, Radiology of Infectious Diseases, https://doi.org/
10.1016/j.jrid.2018.11.002
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Fig. 1. T2 fluid attenuated inversion recovery (T2-FLAIR) MR images show hyperintensity in the corticospinal tracts, especially in the internal capsule. Case
courtesy of A. Prof Frank Gaillard, Radiopaedia.org, rID: 4719.

in clinical assessments. However, routine MRIs are currently concentrated corticospinal fibers (Fig. 1). Subsequent research
only being used to exclude other conditions in the clinical found that other regions of the brain also have signal abnor-
diagnosis of ALS because of technological limitations. Imag- malities, such as hyper-intense signals at the precentral gyrus.
ining technology has grown exponentially, thus, exploration and Recent research by Fabes et al. show that cerebral peduncle
trials have been conducted continuously in ALS [10]. There- intensity provided the strongest subgroup classification [12].
fore, a review is needed to find the possible imaging biologic However, the weakness of T2 weighted imaging is lacking the
markers to help the diagnosis of ALS. This article will sensitivity of the diagnosis of ALS. In conventional T1
comprehensively analyze the application of traditional imaging weighted imaging or even T1 weighted enhanced imaging,
and the latest imaging technology in ALS, especially the latest there are limited abnormalities in ALS patients.
CEST research conducted by our team. In addition, the pros- Another common radiological sign of ALS is known as
pects for the development of ALS diagnosis are forecasted. “motor band sign”, which is hypo-intensity in the precentral
http://www.wfnals.org/downloads/A revision of the El gyrus bilaterally in susceptibility weighted imaging (SWI)
Escorial criteria 2015.pdf. [13](Fig. 2). Although the mechanism was not fully eluci-
dated, pieces of evidence suggested that it may refer to iron
1.1. Conventional magnetic resonance imaging in ALS accumulation within microglia in the motor cortex. However,
the "motor band sign" is not specific for ALS since several
Hyper-intensity on T2-weighted imaging in the cortico- other neurological disorders, such as Alzheimer's disease and
spinal tracts is the earliest discovered sign in ALS, with Parkinson disease, have the same sign [13,14].
specificity <70% and sensitivity <40% [11]. The most obvious Magnetic resonance spectroscopy (MRS) is a non-invasive
lesion was in the internal capsule since it has the most metabolic analytical technique which has been widely used in

Fig. 2. There are low signal intensities on susceptibility weighted imaging (left) in the precentral gyrus bilaterally, and the corresponding high signal intensities on
T2 fluid attenuated inversion recovery imaging (right). Case courtesy of A. Prof Frank Gaillard, Radiopaedia.org, rID: 4717.

Please cite this article as: Dai Z et al., Progress of magnetic resonance imaging in amyotrophic lateral sclerosis, Radiology of Infectious Diseases, https://doi.org/
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Fig. 3. a is MRS of ALS patient, and b is that of normal control group. The decrease of NAA and increase of glutamate is discovered in ALS patients. (Images
courtesy of Journal of Magnetic Resonance Imaging. 2010; 31(2):305-8. with permission of John Wiley & Sons.).

clinical applications. The specific chemical shift in MRS, known experiments [22,23]. Based on the degree of complexity of the
as metabolic peaks in the spectra, can represent the character- diffusion model and sequence, one has different parameters to
ization of tissue. In ALS patients, MRS was reported to be able delineate the microstructure. Among all, the most popular and
to detect metabolic changes in the motor cortex, such as recognized parameters are fractional anisotropy (FA) and
decreased N-acetyl Aspartate (NAA), increased glutamate, apparent diffusion coefficient (ADC). Decreased FA and
increased choline and increased myo-inositol (Fig. 3). Han et al. increased ADC were continuously reported in the corticospinal
discovered that proton MRS could detect neuronal loss and tract of ALS patients (Fig. 4) [24]. FA is a scalar value that
GluþGln increases in the motor area and posterior limb of the describes the degree of anisotropy of a diffusion process. It is
internal capsule of ALS patients [15]. Kumar et al. investigated thought to reflect fiber density, axonal diameter, and myelina-
metabolite profiles in the serum of ALS patients and found tion in white matter. ADC is a measure of the magnitude of
notable changes of metabolism (e.g., glutamate, beta- water diffusion within the tissue. Both the decrease of FA and
hydroxybutyrate, acetate), which could have the potential to increase of ADC indicated the damage of axons and/or myelin
serve as surrogate markers for monitoring ALS disease pro- of white matter fiber tracts which is a significant pathological
gression [16]. The trend of MRS techniques in ALS is from change in ALS.
qualitative to quantitative, from single voxel to multiple voxels, Further research suggested that ADC correlated with dis-
and from low magnetic field to high magnetic field, which is ease duration while FA correlated with disease severity in ALS
becoming more precise and higher in resolution [17,18]. patients [25]. Sage et al. evaluated changes in DTI parameters
in the whole brain of ALS and ascertained that ALS was a
2. Progress of magnetic resonance imaging in ALS multisystem degenerative disease [26]. Filippini et al.
confirmed that corpus callosum was involved and could be a
2.1. Diffusion MRI consistent feature of ALS patients [27]. Another intriguing
observation from Iwata et al. suggested that higher levels of
Diffusion MRI is a series of non-invasive imaging tech- FA within the CST appeared to be linked to slower disease
niques for exploring the diffusion of water molecules in tis- progression [28].
sues, including diffusion kurtosis imaging (DKI), diffusion The application of diffusion imaging in ALS should take
tensor imaging (DTI) and diffusion-weighted imaging (DWI), into account the variation in imaging parameters, such as field
etc. Diffusion is a process by which water molecules move strength, sequence, and post-processing. Huisman et al.
down their concentration gradient, which is an essential inspected that ADC values were statistically significantly
physiological activity of the human body, and diffusion im- lower at the higher magnetic field, while FA values were
aging can reflect early changes in tissue microstructure [19]. elevated [29]. Zhang et al. suggested that inadequate normal-
From DWI to DTI to DKI, the diffusion of water molecules is ization with low-dimensional approaches can result in insuf-
modeling from normal distribution to non-normal distribution, ficient removal of shape differences, which in turn can
and the imaging accuracy of microstructures is also gradually confound FA differences, and utilizing high-dimensional
increased [19e21]. normalization could provide a more comprehensive descrip-
Since diffusion MRI has unique advantages in detecting tion of white matter in ALS patients [30]. Novel diffusion
white matter lesions, it has been extensively used in ALS techniques such as DKI haven't been explored in ALS, which

Please cite this article as: Dai Z et al., Progress of magnetic resonance imaging in amyotrophic lateral sclerosis, Radiology of Infectious Diseases, https://doi.org/
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Fig. 4. (A) The corticospinal tracts (CST) can be reconstructed using diffusion tensor tractography. (B) A scatterplot of the extracted mean CST fractional
anisotropy (FA) against the rate of decline of Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALSFRS) score (points per month) shows a negative
correlation, with potential to prognostically stratify patients. (Adapted from Annals of Neurology 2014 Nov;76(5):643e57. with permission of John Wiley and
Sons).

will be the future diffusion research directions. Meanwhile, are produced in the standardized brain space showing the
post-mortem studies systematically comparing diffusion with location of the voxel clusters where significant between-group
histopathological markers has the potential to improve un- differences in the mean grey matter volumes are present at a
derstanding of how FA, ADC, and other diffusion parameters predefined statistical level of inference. Previous studies have
relate to tract morphology. demonstrated that this quantitative method is precise and
consistent [32].
2.2. Voxel-based morphometry imaging VBM is another progressive technique in ALS imaging
because of its advantage in the quantification of brain atrophy
Voxel-based morphometry (VBM) provides an automated, (Fig. 5). Recent evidence from VBM studies suggests that
voxel-wise comparison of structure volumes between groups central nervous system involvement in amyotrophic lateral
[31]. This procedure involves the normalization of all indi- sclerosis (ALS) extends beyond motor neurons. Mezzapesa
vidual MRI scanning subjects to a standard anatomical space et al. indicated that mild whole-brain volume loss and regional
to remove inter-individual variations in both brain size and frontotemporal atrophy were presented in patients with ALS
shape. The region segments are then compared statistically [33]. A meta-analysis conducted by Chen et al. revealed that
between groups on a voxel-by-voxel basis, and statistical maps right precentral gyrus atrophy might be a specific grey matter

Fig. 5. The voxel-based morphometry (VBM) atrophy of amyotrophic lateral sclerosis (ALS). There is regional grey matter atrophy in the precentral and post-
central gyrus bilaterally, which extended from the primary motor cortex to premotor, parietal and frontal regions bilaterally. Adapted from Grosskreutz J,
Kaufmann J, Fradrich J, Dengler R, Heinze HJ, Peschel T. Widespread sensorimotor and frontal cortical atrophy in Amyotrophic Lateral Sclerosis. BMC Neurol
2006; 6:17 with permission from Creative Commons Legal Code Attribution 2.0 <http://creativecommons.org/licenses/by/2.0/legalcode>.

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volume deficit pattern for ALS [34]. Assessing brain volume examinations of VBM and 18[F]-fluorodeoxyglucose (FDG)
change with VBM depends significantly on the segmentation PET. Recent provocative research conducted by Buhour et al.
and normalization procedures [31]. Therefore, relatively large provided direct evidence of regional variations in the hierarchy
sample sizes should be carried out in future VBM studies. and relationships between GM atrophy and hypo-metabolism
in ALS [52]. Another original study by Menke et al.
2.3. Chemical exchange saturation transfer imaging revealed novel longitudinal functional connectivity insights in
ALS by analyzing multimodality MRI data including VBM,
Chemical exchange saturation transfer (CEST) is a novel DTI, and resting-state functional MRI [53]. It is worth noting
imaging technique that can show specific metabolites with high that multimodality must be an effective integration, not merely
resolution and high sensitivity [35e38]. More importantly, a combination of multiple technologies. Only by leveraging
CEST can detect substances that are silent in MRS [39e41]. full features of advanced imaging techniques, one can increase
The mechanism of CEST is based on the chemical exchange the diagnostic accuracy and sensitivity.
between targeted protons and water protons. A specific irradi- The development of innovative technologies is also critical
ation pulse is applied to saturate the specific target, and the to improving the diagnosis of ALS. We believe CEST is a very
saturation effect is amplified through the chemical exchange competitive technology, which has a particular niche in the
process [38]. There are several advantages with utilizing this detection of metabolism [54]. Based on our primary study,
mechanism. The first and most important one is maintaining the CEST is likely to be a diagnostic biomarker for ALS. Since no
stability of the internal environment without contrast agent contrast agents were used in CEST, it is supposed to reflect
interference. Additionally, the technique has considerable per- true pathological changes, which will be more powerful with
formance in terms of spatial resolution and sensitivity [42]. the high strength magnetic field such as 7 T [55]. The com-
CEST has extensive promising applications in neuro sys- bination of CEST and DTI will provide a phenomenal tool to
tems since it has unique advantages [43]. CEST amide imag- detect neurochemical and microstructure simultaneously.
ing, also known as amide proton transfer (APT) imaging, has Machine learning is another versatile technique in the
been proven to differentiate the benign and malignant tumors prospect of ALS diagnosis. Machine learning is a method of
of the nervous system [44]. A recent exhilarate study indicated data analysis that can automate the image classification pro-
that CEST amide imaging can even distinguish tumor recur- cess without human intervention. It has been applied to
rence and radiation necrosis, which was of significance in the medical images and has helped in improving medical diag-
clinic [45]. CEST glutamate imaging, CEST pH imaging, and nosis [57]. A recent study conducted by Van der Burgh et al.
several other metabolite imaging were also proven to be ver- demonstrated that machine learning is predictive for ALS
satile tools for neuro disease diagnosis [46e48]. However, the survival using structural connectivity MRI data [56]. Future
application of CEST in ALS has not yet been explored. ALS research will be based on multi-center and big data, for
Since the neuro-degeneration and metabolic reprogram- which machine learning has inherent advantages.
ming in ALS [49], we hypothesize that CEST imaging could In conclusion, this article systematically reviewed the role
be a new image biomarker in ALS diagnosis. After a pre- of magnetic resonance imaging in amyotrophic lateral scle-
liminary study in five ALS patients, we found that CEST rosis. MRI can provide useful insights into the diagnosis of
signal is significantly different between motor cortex and ALS. Different techniques have different perspectives of the
control grey matters. The signal intensity of CEST in motor disease, of which DTI is currently the most commonly used
cortex was reduced in ALS patients, which indicatedthe dis- technology. However, there is no absolute diagnostic imaging
order of neuron and/or myelin because the change of CEST method for ALS, and effective multimodality can increase the
usually represents the alteration of intracellular protein that diagnostic accuracy. In addition, the novel technique such as
has an intimate relationship with cell activity and proliferation CEST was first mentioned in this article. We believe that with
[45,50]. These results were also supported by previous a MRS the maturity of these novel MRI technology and multimodality
study which detected the reduction of N-acetylaspartate in the imaging, objective imaging biomarkers will be found in ALS.
motor cortex [25]. In conclusion, our study detected changes
in the motor cortex of ALS using a CEST imaging technique, Acknowledgements
which may have the potential to be an imaging biomarker for
the diagnosis of ALS. This study was supported in part by grants from the Natural
Science Foundation of Guangdong Province (2017A030307020,
2.4. Prospect of magnetic resonance imaging in ALS 2018A030307057) and National Natural Science Foundation of
China (81471730, 31870981).
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Please cite this article as: Dai Z et al., Progress of magnetic resonance imaging in amyotrophic lateral sclerosis, Radiology of Infectious Diseases, https://doi.org/
10.1016/j.jrid.2018.11.002