The ALS Association

Ice Bucket Challenge Progress

New ALS Research at the American Academy of Neurology

May 22, 2014

Important advances in ALS were featured at the Annual Meeting of the American Academy of Neurology (AAN), held in April. Among the highlights:

Presymptomatic Imaging Changes in SOD1 Gene Carriers
A neuroimaging study revealed that people carrying the ALS-causing mutant SOD1 gene have subtle structural changes in the brain’s white matter years before likely disease onset. White matter refers to the axons, or insulated extensions of neurons, that carry information from one brain region to another. By comparing images between gene carriers and non-carriers, the researchers found changes affecting the right temporal lobe, a region on the brain’s surface near the ear. Surprisingly, this region is not involved in motor functions, as might be expected in a motor neuron disease such as ALS. The significance of these changes is not yet clear, but they suggest that the ALS disease process, at least in those carrying the SOD1 gene, may begin long before symptoms become apparent. The ability to detect such changes will be important for beginning treatment as early as possible, once a disease-modifying therapy is developed.

New ALS Risk Gene Points to Neuroinflammation
A variant in a gene that promotes inflammation in the central nervous system more than doubles the risk for ALS, according to new research. The gene, called TREM2, activates microglia, immune system cells in the brain and spinal cord. The variant, which causes a switch of one amino acid in the TREM2 protein, has been associated with an increased risk of Alzheimer’s disease. Here, the authors sequenced the gene in almost 1,000 people with ALS and 2,000 controls. They found that the variant was 2.4 times as common in those with ALS versus controls, and that there was more TREM2 protein than expected in the spinal cord of those with ALS and in SOD1 mutant mice, suggesting that dysregulation of the gene contributes to disease. An increase in inflammation may accelerate the disease process.

C9orf72 Expansion Binds Multiple RNA Binding Proteins, Alter RNA Splicing
The mutant expanded portion of the C9orf72 gene binds to more than 100 proteins, according to new research. The authors found that among the proteins that were bound by the expansion were many involved in RNA splicing, the process that edits the “working copy” of a gene before making protein from it. Altered splicing is thought to play a role in ALS. They also found that some of these splicing proteins were mislocalized in tissue from people with ALS. These results suggest that the gene mutation causes ALS at least in part by significantly altering the splicing process. This may lead to better understanding of the disease process and identification of new targets based on correction of splicing abnormalities.

New Results from the National ALS Registry
In 2010, with critical advocacy support from The ALS Association, the federal Agency for Toxic Substances and Disease Registry (ATSDR) launched the National ALS Registry. The purposes of the ALS Registry are to:  identify ALS cases nationwide; increase understanding of what causes ALS; identify the incidence, prevalence, and distribution of the disease; improve diagnosis and clinical care; and ultimately help to find a treatment for the disease.

The ALS Registry combines data from existing national databases, such as those from the Department of Veterans Affairs and the Medicare and Medicaid programs, with self-reported data from people with ALS.  Ten studies connected to the ALS Registry were featured in poster sessions at the meeting. Results presented included:

  • About 20 percent of neurologists nationwide diagnosed or cared for a person with ALS in the past three years.
  • Most people with ALS receive care at a large metropolitan specialty center.
  • Accuracy of diagnosis by general neurologists was close to that of ALS specialists.
  • There are approximately 5,000 new cases of ALS diagnosed in the U.S. every year.

The Registry will continue to provide important data for ALS research including for tracking ALS in the US over time, for better understanding regional patterns of disease that may be linked to environmental or occupational risks and for identifying risk factors for the disease.

Latest Data on Tirasemtiv Indicates Promise, Problems
As detailed in the report from the Drug Company Working Group meeting, the recent trial of tirasemtiv showed that prolonged treatment at high doses improved muscle strength and some measures of breathing but did not improve overall function as measured by the ALS Functional Rating Scale. More data analysis is ongoing to better understand the results of this trial and to determine how to proceed with development of the drug.

Essey Award Session Features Latest and Previous Recipients
As further detailed in this article, Jeremy Shefner, M.D., Ph.D., received the 2014 Sheila Essey Award from The ALS Association and the American Academy of Neurology, for a career dedicated to ALS clinical research. The session featured a talk by Dr. Shefner on the development of biomarkers for tracking disease progression and response to therapy, as well as some of the latest research on ALS. It concluded with a whirlwind round of presentations from many of the past recipients of the Award, outlining progress on many fronts in the struggle to understand and treat ALS.

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