When Nigel Leigh started scanning the brains of people with amyotrophic lateral sclerosis (ALS) in the early 1990s, colleagues said he was wasting his time. “You’ll find nothing,” they told Leigh, who is now at King’s College London, U.K. The imaging techniques that have provided a wealth of data and scientific inspiration related to Alzheimer’s and other neurodegenerative disorders, researchers thought, would be useless for a motor neuron disease, where all the trouble was thought to be in the spinal cord.

But Leigh and a small cadre of like-minded scientists persisted, and today, imaging for ALS has earned some respect, with a small but steady stream of data flowing out of their magnetic resonance imaging (MRI) and positron emission tomography (PET) scanners. Amid that data stream is a paper Leigh, with first author Biba Stanton, also of King’s College London, and colleagues published in the January issue of the Archives of Neurology. It describes differences in the brain images of participants with different forms of ALS—differences that might eventually be useful in defining kinds of ALS in the clinic, he said.

“It’s doing neuropathology in vivo,” said Martin Turner, a former student of Leigh’s who now works at Oxford University, England. Over time imaging technology has become more sophisticated, allowing researchers to probe the brain more deeply. These tools have proved that neurons in the brain, too, are subject to damage in ALS. As imaging and analysis methods continue to advance, some scientists want to peer into the spinal cord, a goal that had been considered impossible for such a skinny organ. Ultimately, scientists hope to find a visible signal that will allow objective diagnosis and tracking of disease progress in clinical trials.

In today’s ALS clinic, imaging plays a minor supporting role. Doctors frequently use MRI during a diagnostic workup to exclude other possible causes for a person’s symptoms. A tumor, vascular disease, or compression or degeneration of the spine, could all mimic ALS. These would be visible irregularities, whereas a person with ALS is likely to have a normal-looking scan.

In contrast to the ALS field, imaging has garnered plenty of attention—and research dollars—for other neurodegenerative conditions such as Alzheimer disease (AD). The changes in an AD brain are obvious; atrophy of the temporal lobes, for example, is hard to miss. The National Institutes of Health and private donors are jointly funding the Alzheimer’s Disease Neuroimaging Initiative, a five-year study to follow more than 800 people with and without AD over three years, tapping a collection of imaging techniques and fluid biomarkers and comparing them side by side. Midway through the project, data are already pouring out via scientific literature and conference presentations (see ARF related news story).

Brain imaging in ALS is just getting started. The ALS field lacks the large patient cohorts that AD researchers can assemble, and the neural changes are subtler. One thing the field has going for it is that people with ALS are generally enthusiastic about participating in research. “They will do anything they can to help with the study,” said Erik Pioro of the Cleveland Clinic in Ohio. In contrast, in AD research, impaired ability to provide informed consent can complicate enrollment.

However, as people with ALS get sicker, it becomes too difficult for them to travel to the hospital. In one study, Leigh said, half of his patients dropped out within six months. Some people with ALS have difficulty swallowing or breathing, which rules out lying flat in an MRI scanner for 40 minutes or more. Pioro, therefore, dreams of using a vertical MRI machine. Technically, this is certainly possible. Small vertical scanners are used for imaging a standing leg, for example, and at least one research group uses one for seated monkeys, Pioro said, but no company has developed a human-sized upright version.

ALS Across the CNS
ALS, a disease of motor neurons, was once thought to cause pathology primarily, even exclusively, in the spinal cord. Though the brain’s involvement is obvious in some cases, such as when ALS is found in conjunction with frontotemporal dementia, generally the only symptoms come from motor neuron degeneration (Woolley and Katz, 2008). One of the early contributions imaging made to ALS research was to show that the disease does not stop at the neck. In a 1994 paper, MR spectroscopy showed low levels of the neural metabolite N-acetyl-aspartate in people with ALS, particularly in the primary motor cortex, suggesting a neural deficiency (Pioro et al., 1994). Scientists have also found shrinkage of white and grey matter, particularly in people who exhibit ALS with cognitive impairment (Abrahams et al., 2005; Chang et al., 2005; Grosskreutz et al., 2006). But neuronal degeneration is evident even in ALS patients without dementia (Turner et al., 2005).

Despite this imaging research, so far nothing stands out as characteristic of all people with ALS. Much as scientists wish for it, there is no biomarker, no big neon sign proclaiming “ALS Here.” Diagnosis based on clinical symptoms can take months, delaying people’s seeking appropriate treatment or enrolling in clinical trials during the early stages of disease. The lack of a biomarker also inhibits drug research. Currently, researchers testing potential therapeutics rely on survival rates and indirect measures of disease such as lung capacity, speech, and handwriting.

“The beauty of MRI is that it’s an objective measure,” said Norbert Schuff of the University of California, San Francisco. “It’s a physical measure like your body temperature; you cannot fake it.” In contrast, evaluations such as the ALS Functional Rating Scale depend on subjective ratings of a person’s abilities. As in AD research, a good biomarker would increase a study’s statistical power, Schuff noted, allowing trials to proceed with fewer patients or a shorter timeline. However, MRI technology and protocols vary widely among hospitals, meaning it would be difficult to compare patients from different facilities to each other. (This was also an issue in developing standardized protocols for the 56 centers that participate in ADNI.)

Currently, one of the most promising techniques for imaging ALS-specific pathology is diffusion tensor imaging (DTI), said experts interviewed for this story. DTI records the diffusion of the protons in water molecules through tissues. This allows scientists to image nerve fibers indirectly. A tightly bound bundle of axons will inhibit crosswise flow of water; when those axons degenerate, water can get through more easily and the image changes accordingly. Water diffusivity is greater in people with ALS (Ellis et al., 1999).

As technology advances and scanners achieve smaller and smaller spatial resolution, scientists are also starting to reconsider imaging the spinal cord. “I think that’s probably our best chance for a marker for early disease,” Turner said. The spinal cord is only millimeters in diameter; that corresponds to at most a few voxels with current imaging techniques. (A voxel is a 3-D pixel.) Bones also get in the way of quality imaging. However, Turner hopes that with stronger magnets and advanced technology, one could get a decent picture of the site where ALS wreaks most of its havoc. Spinal cord DTI, he anticipates, might reveal fiber disruption, perhaps even before clinical symptoms present.

My ALS Is Not Like Yours
The clinical diagnosis “ALS” refers to a collection of symptoms, but the underlying causes may be different in different people. Some inherit a gene that causes ALS, but for most cases the root cause is a mystery. The course that the disease takes also varies. For example, most people with ALS die within a few years of developing symptoms, but some may survive a decade or more. If scientists were able to use imaging to sort ALS into tidy categories, they might find that treatments work differently on people with different kinds of disease, Leigh said.

In their January paper, Leigh and Stanton illustrated that point by comparing DTI images of people with sporadic ALS and people with a specific familial form, i.e., the D90A mutation in superoxide dismutase 1 (SOD1). Participants were matched for disease severity and upper motor neuron symptoms. People with sporadic ALS showed more white matter damage throughout the brain, in the corpus callosum and in both motor and non-motor pathways, than did the mSOD1 carriers. Among the people with sporadic ALS, measures of water diffusivity correlated with their level of disability. The study, Leigh said, proves that scientists can use imaging to distinguish different patterns of axonal damage in people with the same diagnosis.

This kind of research could someday give imaging a more prominent role in the clinic, as well as in the lab. If scientists could tease out the classes of images that match different disease courses, doctors could use that information to make prognoses and prescribe appropriate interventions. For example, Turner said, patients who are likely to develop breathing problems might benefit from early use of a breathing assistance device. Some, he suggested, might even elect implantation of a diaphragm stimulator, a pacemaker for the breathing muscles. Similarly, if a patient is likely to face swallowing problems, he or she might consider a feeding tube. Implanting one requires sedation, which is not an option for people who also struggle to breathe. That means people with ALS should consider the feeding tube before they truly need it, but some put off the decision. “It’s a real tragedy when the patient has waited too long and we can’t put it in,” Turner said. The non-surgical alternative at this point, a nasal feeding tube, is uncomfortable and a poor long-term solution, he said.

These lines of research are beginning to paint a picture of ALS. The field remains fraught with fundamental challenges, but it also holds potential to study the structural components of the disease in a way that no other technique can offer. The value of imaging in ALS is “just beginning to be realized,” Leigh said. Stay tuned, then, for more detailed portraits of this many-faceted disease.—Amber Dance


No Available Comments

Make a Comment

To make a comment you must login or register.


Paper Citations

  1. . Cognitive and behavioral impairment in amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am. 2008 Aug;19(3):607-17, xi. PubMed.
  2. . Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology. 1994 Oct;44(10):1933-8. PubMed.
  3. . Frontotemporal white matter changes in amyotrophic lateral sclerosis. J Neurol. 2005 Mar;252(3):321-31. PubMed.
  4. . A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD. Neurology. 2005 Jul 12;65(1):75-80. PubMed.
  5. . Widespread sensorimotor and frontal cortical atrophy in Amyotrophic Lateral Sclerosis. BMC Neurol. 2006;6:17. PubMed.
  6. . [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain. 2005 Apr;128(Pt 4):896-905. PubMed.
  7. . Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology. 1999 Sep 22;53(5):1051-8. PubMed.

Other Citations

  1. ARF related news story

Further Reading


  1. . Can we use diffusion MRI as a bio-marker of neurodegenerative processes?. Bioessays. 2008 Nov;30(11-12):1235-45. PubMed.
  2. . A longitudinal diffusion tensor MRI study of the cervical cord and brain in amyotrophic lateral sclerosis patients. J Neurol Neurosurg Psychiatry. 2009 Jan;80(1):53-5. PubMed.
  3. . Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Sep;5(3):141-9. PubMed.
  4. . Neuronal loss associated with cognitive performance in amyotrophic lateral sclerosis: an (11C)-flumazenil PET study. Amyotroph Lateral Scler. 2008 Feb;9(1):43-9. PubMed.
  5. . Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: a clinical and brain imaging review. Neuromuscul Disord. 2009 Jan;19(1):53-8. PubMed.
  6. . Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 2009 Jan;8(1):94-109. PubMed.
  7. . Multimodal Magnetic Resonance Imaging for Brain Disorders: Advances and Perspectives. Silence. 2008 Nov 1;2(4):249-257.
  8. . Longitudinal assessment of grey matter contraction in amyotrophic lateral sclerosis: A tensor based morphometry study. Amyotroph Lateral Scler. 2009 Jun;10(3):168-74. PubMed.

Primary Papers

  1. . Diffusion tensor imaging in sporadic and familial (D90A SOD1) forms of amyotrophic lateral sclerosis. Arch Neurol. 2009 Jan;66(1):109-15. PubMed.