INSIDE
RESEARCH ALS TODAY THE ALS ASSOCIATION
VOLUME 12
Neurofilaments Sheila Essey Award ALS Clinical Trial Update AAN/ALS Clinical Fellow Journal News
SPRING 2013
Neurofilaments as Potential Biomarkers for ALS Kevin Boylan, M.D. Department of Neurology, Mayo Clinic, Jacksonville, Florida and Medical Director, The ALS Association Certified Center
Wide variation in the rate of progression and survival are recognized characteristics of amyotrophic lateral sclerosis (ALS), and estimation of prognosis and monitoring of clinical progression are of central importance in patient care and clinical research. Assessment of the progression of ALS presently relies on clinical outcome measures, such as functional rating scales and tests of muscle strength, because there are no direct tests of nerve damage that have proven reliability. There is a strong need for disease biomarkers in ALS that demonstrate greater sensitivity to disease progression and survival than those presently available.
Development of tests that can identify and track molecular indicators of disease activity, or biomarkers, in cerebrospinal fluid (CSF) and peripheral blood in ALS has been a focus of recent research at several centers worldwide, but no biomarkers of this kind have as yet been fully validated for use in clinical practice or clinical trials. Tests of this kind could offer more sensitive and efficient ways to measure progression of ALS, provide more direct ways to evaluate the effectiveness of new medications and potentially facilitate the process of establishing the diagnosis of ALS.
Candidate markers of nerve cell damage in ALS include biomarkers linked to degeneration of motor neurons, such as the subunits of neurofilaments, major structural components of neurons. Three major protein subunits of neurofilaments are designated heavy (NF-H), medium (NF-M) and light (NF-L) subunits on the basis of molecular weight. These neurofilament subunits are heavily concentrated in large motor axons, and neurofilament subunits are expected to be released in significant quantities following axonal damage or degeneration. Several research groups reported that concentrations
of NF-H and NF-L are increased in CSF in ALS compared with healthy subjects and patients with other neurological disorders, supporting the concept that elevated pNF-H and NF-L concentrations may be useful biomarkers in ALS. Of particular importance were early reports that the concentrations of pNF-H and NF-L in CSF may correlate with the rate of disease progression and survival in ALS. Interest in NF-H as a potential ALS biomarker is based in part on structural characteristics of the protein that confer enhanced stability in CSF and Continued on page 6
NEUROFILAMENT SUBUNITS Neurofilament subunits are rod-like proteins found in nerve cells. Of the three neurofilament subunits, NF-H contains the longest series of lysine-serineproline tandem repeats. In motor axons these repeats tend to be modified by attachment of phosphorous, referred to as phosphorylation. Phosphorlyation confers resistance to normal breakdown processes and appears to make pNF-H more stable in peripheral blood and CSF, a useful property in clinical testing. Degeneration of motor neurons releases pNF-H into the CSF and peripheral blood stream, where its concentration can be measured. Kevin Boylan, M.D.
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