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Scientists funded by ALSA are seeking biomarkers that will provide earlier diagnosis of ALS and will help in designing decisive clinical trials of new drugs. Biomarkers are those molecules or structures in the body that can define a particular condition. Biomarkers that are present only in the disease state, or that change appreciably with the disease, would be a chemical signature that clinicians could read in a sample of blood or other easily obtained body fluid, such as that which bathes the spinal cord and brain, called the cerebrospinal fluid (CSF). ALSA is funding a consortium effort, enlisting leading researchers and biotech companies in the search for reliable biomarkers of ALS.

What are Biomarkers?

According to the "central dogma" of molecular biology as seen in the figure to the right, DNA is transcribed into RNA then translated to proteins, which then make small molecules. While there may be over 25,000 genes, 100,000 to 200,000 transcripts and up to 1,000,000 proteins, it is estimated that there may be as few as 2,500 small molecules in the human metabolome.

Biomarkers are by definition an indicator of a particular condition in the body. They can be any entity that changes in quantity or that appears or disappears with a change in the body's state. Diseases such as ALS that are extremely difficult to diagnose by the usual means of blood or urine tests or by physical examination would be revealed by a validated set of biomarkers, molecules that change concentration, or appear or disappear, with the disease, or structures that are altered by the disease. What could serve as a biomarker for ALS?

Researchers funded by ALSA are seeking proteins that exist in cells or are secreted by cells, or any other product of metabolism, that would change with ALS. It is likely that, for molecules, several would have to be changing in concentration or be differentially present or absent to accurately reflect ALS.

Methods now available make it possible to analyze very small amounts of fluid collected from living beings. Charged surfaces of protein binding chips can separate all the different proteins found in the blood or in the cerebrospinal fluid (CSF) that bathes the brain and spinal cord, or in urine or other body secretions. Investigators can use an extremely sensitive technique to identify the separated molecules, called mass spectrometry. The initial results from investigations show that certain molecules are indeed decreased in CSF in ALS, and others increase. But these potential biomarkers must be verified as accurate indicators of the disease before they can be made into a diagnostic test.

Other routes to a biomarker of ALS would be imaging studies, if these can show that certain changes in the brain or spinal cord accompany the disease and are specific to ALS. New imaging methods promise the specificity and sensitivity that are required to produce an ALS diagnositic. Any measure that changes with ALS and is specific for ALS, and will not confuse ALS with another disorder, could serve as a biomarker for the disease.

By analyzing a sample using multiple mass spectrometry-based technologies, integrating the data and analyzing through proprietary software and algorithms, our scientists can develop an understanding of a disease state much faster and more accurately than previously possible. Image provided by Robert Bowser, Ph. D., University of Pittsburgh School of Medicine

Biomarkers for ALS: Current Investigations

Project title: Identification of Diagnostic Biomarkers and Therapeutic Targets for ALS

Cudkowicz, Merit, M.D., MPH, Massachusetts General Hospital, Boston

Bowser, Robert, Ph.D., University of Pittsburgh School of Medicine

Brown, Robert, M.D., Ph.D., Massachusetts General Hospital, Boston

Kaddurah-Daouk, Rima, Ph.D., Duke University, Durham, N.C.

Paige, Lisa, Metabalon Inc, Research Triangle Park, N.C.

Diagnostic biomarkers are any small molecules that can be detected in the blood or cerebrospinal fluid (CSF) and are associated with a disease. Biomarkers would enable earlier and accurate diagnosis of ALS, with a greater chance for earlier treatment to alter the disease course. Biomarkers would also make it possible to measure the effectiveness of different drug treatments in clinical trials. A set of 19 proteins has shown promise as a biomarker panel for ALS. The investigators will continue testing samples with a focus on CSF, since the highest level of biomarkers may occur there. In addition, they will focus on biomarkers detected in ALS patients that have not received riluzole, since a diagnostic for ALS will likely be for people not yet receiving an ALS medication. Importantly, the researchers will seek the identity of the protein and metabolic biomarkers that appear to be specific to ALS. This will help explain the molecular reasons for the disease and inform the search for potential drug treatments.

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