ARTICLE IN BRIEF
In a small trial, patients who have the superoxide dismutase 1 variant were found to have white matter abnormalities in a non-motor area on MRI before the onset of amyotrophic lateral sclerosis.
PHILADELPHIA—Individuals with mutations in the superoxide dismutase 1 (SOD1) gene develop brain white matter abnormalities before the onset of symptoms of amyotrophic lateral sclerosis (ALS), according to a new imaging study that was presented here at the AAN Annual Meeting in April. Surprisingly, the changes are in a non-motor area of the brain, leaving researchers to wonder whether they signify a previously unsuspected site of disease onset, or a change with no necessary pathogenic relation to the future neurodegenerative process expected in these individuals.
The concept of a pre-symptomatic phase in neurodegenerative diseases has developed out of the ability to detect imaging changes in individuals with genetic forms of Alzheimer's, Parkinson's, and Huntington's diseases. In each case, individuals carrying those gene mutations develop the characteristic imaging abnormalities years and, in some cases, decades before clinical onset.
In ALS, the first such studies are just now emerging. Michael Benatar, MD, PhD, FAAN, an associate professor of neurology at the University of Miami in Florida, has led this effort. He is conducting a longitudinal study of pre-symptomatic individuals with familial ALS. Originally focused on the SOD1 gene, the first gene known to cause ALS, it has expanded in the seven years since its inception to include all genetic forms of ALS. Individuals at risk obtain a genetic test; if they are gene-positive, they are enrolled. Some family members are interested in the project but don't wish to know their gene status; they can also enroll, and remain in the study without learning their status, acting as familial controls if they are gene-negative. There are currently over 70 gene-positive individuals enrolled.
“One of the principal goals of the longitudinal study is to learn how to predict when a person is likely to clinically manifest,” Dr. Benatar said. “That requires extensive testing before conversion and long enough follow up to provide a sufficient number of individuals who develop clinical ALS.”
In the current study, 32 SOD1-positive individuals who were symptom free an unknown number of years before their expected clinical conversion underwent MRI diffusion tensor imaging using a 3 Tesla magnet. The age at onset for individuals with an SOD1 mutation varies enormously, even among family members carrying the same mutation. Also tested were 31 SOD1-positive individuals who had developed ALS, and 34 healthy controls. The average age for each group was 49 to 50 years.
The lead study author, Martin Turner, MD, PhD, a consultant neurologist and senior clinician scientist within the Oxford University Nuffield department of clinical neurosciences, performed the imaging analysis.
The “headline result,” Dr. Turner said, was that pre-symptomatic individuals “displayed a region of significantly increased axial diffusivity along the temporal lobe projection tracts on the right side, an area of pathology also observed among the ALS patients.”
Axial diffusivity, he explained, is a mathematical measure related to aspects of water movement through the brain. It is influenced by myelin integrity and packing density, “but we have much more work to do to understand what these measures mean pathologically.”
Exploratory lowering of the statistical threshold did not reveal contralateral or more widespread pathology in the pre-symptomatic group, Dr. Turner said.
Remarkably, this change in axial diffusivity was in a non-motor area. While some forms of ALS, most notably those due to the C9orf72 (chromosome 9 open reading frame 72) gene, often include prominent non-motor features, SOD1 ALS does not.
Motor area involvement was seen in affected ALS patients, but not pre-symptomatic individuals, when compared with controls. Changes were also seen in the inter-hemispheric motor fibers of the body of the corpus callosum.
“What does it mean? We have more questions than answers at the moment,” Dr. Turner said. “I can tell you something is wrong,” but what it may be is unclear. “Whether it is a marker of pathology is not yet known,” he added.
Longitudinal neuropsychological testing results, which Dr. Benatar has collected for enrolled individuals, have not yet been examined in light of these findings.
Neither do these results yet shed light on the length of the pre-symptomatic phase in ALS. While two individuals in the study converted to ALS after their scans, the numbers are still too small for prognostics regarding time to conversion based on imaging.
Dr. Turner noted that Yankee baseball player Lou Gehrig's batting average remained remarkably steady during the latter years of his career, and then dropped off abruptly, shortly before his death, suggesting a very short pre-symptomatic period. Calculations based on the post-diagnosis rate of the loss of motor units over time in patients suggest the same. Nonetheless, he said, “I think most of us think it is likely to start much before diagnosis.”
That length may matter if, as is suspected, disease-modifying drugs will only be maximally effective during that period. “The ultimate goal is a disease prevention trial,” Dr. Benatar said, which would be based on a prediction of when an individual patient is likely to convert.
Most intriguingly, what might it mean that the first observable change occurs outside the motor areas? “Increasingly, we think of ALS as a network degeneration,” he said, with disease spreading from “kindling regions” to other connected areas. But whether the right temporal lobe represents such a region is unknown. “At this point we remain agnostic to that question. What we need is to extend the longitudinal follow-up. Although we have been doing this for a while, we are still just scratching the surface.”
“I think it is an important finding,” said Nazem Atassi, MD, an assistant professor of neurology and associate director of the Neurological Clinical Research Institute at Massachusetts General Hospital in Boston. “It is very novel, interesting, and puzzling,” given the early involvement of a non-motor area. Understanding the significance of the changes will only come by observing how they change over time, until diagnosis. Whether they are related to the motor degeneration, or represent a clinically unimportant epiphenomenon, won't be clear without longer follow-up, he said. In any event, the identification of a reproducible imaging change in SOD1 ALS may allow researchers to track its evolution during therapy, for instance with antisense therapy against the SOD1 gene, which has been shown to be safe in patients with the disease, and which is being developed further. “This is where the neurodegenerative field is going.”
This study was selected by members of the Neurology Today editorial advisory board as one of the noteworthy papers from the AAN Annual Meeting.