It is easy to confuse one motor neuron disease for another: amyotrophic lateral sclerosis, primary lateral sclerosis, and lower motor neuron disease can all mimic each other. But each has a slightly different prognosis, and those distinctions will be even more important if and when disease-specific therapeutics arise. The race to find a good biomarker to make diagnoses or track disease progression (see ARF related news story on Gordon et al., 2009) has yielded many ideas, but no real winners yet (see ARF related news story). In a preliminary study published in Neurology March 23, researchers from Ulm University in Germany offer a trio of biomarkers from cerebrospinal fluid (CSF) that might help differentiate these pretenders.

Amyotrophic lateral sclerosis (ALS), incorporating both upper (brain) and lower (spinal cord) motor neuron symptoms, is the most common form of motor neuron disease (MND). But it can start in either the upper or lower motor neurons alone, and thus look similar to the conditions that affect just one section. Of the MNDs, ALS has the worst prognosis, with a three- to five-year life expectancy once symptoms arise. Therefore, an accurate and early diagnosis could provide useful information to patients and their families.

To differentiate the conditions, the researchers, led by first author Sigurd Süssmuth and principal investigator Hayrettin Tumani, performed lumbar spinal taps on 122 people with MND. Several had their diagnoses change during the seven-year follow-up period, but at the end, 102 had an ALS diagnosis; 12 had lower motor neuron disease (LMND), such as progressive muscular atrophy; and eight had upper motor neuron disease (UMND), either primary lateral sclerosis or hereditary spastic paraplegia. A control group consisted of 28 people with tension headache.

Süssmuth and colleagues focused part of their analysis on tau, an axonal protein. Its release into the CSF would indicate axon degradation. Other research groups have explored tau as a potential biomarker for Alzheimer disease and aging (see ARF related news story on Stomrud et al., 2010 and Fjell et al., 2010). In the current study, tau levels were high in the CSF of people with ALS and UMND, compared to LMND and control subjects. The results “make sense,” said Gerry Shaw, of the McKnight Brain Institute in Gainesville, Florida, who was not involved in the study. One might predict, he said, that tau leaking from damaged neurons in the upper part of the body would flow downward and show up in a lumbar puncture, while tau from damaged lower neurons would be less likely to travel to the lumbar area.

The authors also measured immune system indicators. Immune system activity, both protective and harmful, has been linked to ALS in several studies (see ARF related news story; ARF related news story on Chiu et al., 2009; and ARF related news story on Gowing et al., 2008). To assess the changes in the immune system, Tumani and colleagues measured S100β, an indicator of astroglial activation, and sCD14, a monocyte receptor involved in neuroinflammation. CSF S100β levels were lower in the LMND subjects than in ALS or UMND subjects, and sCD14 quantities were low in CSF of both ALS and LMND participants, compared to the other groups. These markers also provided some hints about a person’s prognosis. Low CSF S100β, but high cSD14, correlated with longer survival in people with ALS.

Biomarkers are a topic of interest across the neurodegenerative disease field, but have been hard to pin down (see ARF related news story). “It is difficult to get all your ducks in a row in order to do this kind of work,” Shaw said. CSF is an obvious place to look for molecules or proteins indicating nerve dysfunction, but there are a host of problems in analyzing it, note Merit Cudkowicz of Massachusetts General Hospital in Boston, and Michael Swash of the Royal London Hospital in the United Kingdom, in an editorial accompanying the Neurology paper. CSF does not circulate quickly, they write, and so its composition might vary depending on which part of the spine is tapped, what time of day the procedure takes place, and the foods, drugs, or medication the person has been using at the time. Even the temperature of sample storage and freezing method can alter results. A spinal tap is also a painful procedure, Shaw said. He believes blood will be a more useful fluid since it is easy to access both in people and in small animal models, where more than one CSF sample may be impossible to obtain. However, Shaw noted that blood also presents difficulties, since it contains so many concentrated proteins that could complicate analysis.

Süssmuth and coauthors suggest that their biomarkers may be useful to make prognoses in people with motor neuron disease, but are quick to point out that a larger study is necessary to validate the data. A longitudinal study with multiple spinal taps over time would also be useful, Shaw said. Cudkowicz and Swash note that the biomarker changes in the current study are not necessarily ALS-specific. “The search for an elusive diagnostic test must therefore continue,” they write.—Amber Dance


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News Citations

  1. Seeking a Reliable Yardstick for ALS Trials
  2. News Brief: Scientists Net Prizes for Progress Toward ALS Biomarker
  3. CSF Biomarkers Track With Atrophy, Cognition in Normal Aging
  4. ALS: T Cells Step Up
  5. Peripheral Innate Immunity—Not So Peripheral to ALS?
  6. Microglia in ALS: Helpful, Harmful, or Neutral?
  7. Uppsala: Brainstorming Biomarkers

Paper Citations

  1. . Defining survival as an outcome measure in amyotrophic lateral sclerosis. Arch Neurol. 2009 Jun;66(6):758-61. PubMed.
  2. . Correlation of longitudinal cerebrospinal fluid biomarkers with cognitive decline in healthy older adults. Arch Neurol. 2010 Feb;67(2):217-23. PubMed.
  3. . CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease. J Neurosci. 2010 Feb 10;30(6):2088-101. PubMed.
  4. . Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20960-5. PubMed.
  5. . Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci. 2008 Oct 8;28(41):10234-44. PubMed.

Further Reading


  1. . Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker. J Neurochem. 2009 Dec;111(5):1182-91. PubMed.
  2. . Molecular imaging of neurodegeneration by a novel cross-disease biomarker. Exp Neurol. 2009 Sep;219(1):274-83. PubMed.
  3. . Immune blood biomarkers of Alzheimer disease patients. J Neuroimmunol. 2009 May 29;210(1-2):67-72. PubMed.
  4. . Applying proteomics to the diagnosis and treatment of ALS and related diseases. Muscle Nerve. 2009 Nov;40(5):753-62. PubMed.
  5. . Cystatin C in cerebrospinal fluid as a biomarker of ALS. Neurosci Lett. 2009 Mar 6;452(1):52-5. PubMed.
  6. . S100-mediated signal transduction in the nervous system and neurological diseases. Cell Mol Biol (Noisy-le-grand). 2005 Sep 5;51(2):201-14. PubMed.

Primary Papers

  1. . CSF glial markers correlate with survival in amyotrophic lateral sclerosis. Neurology. 2010 Mar 23;74(12):982-7. PubMed.
  2. . CSF markers in amyotrophic lateral sclerosis: has the time come?. Neurology. 2010 Mar 23;74(12):949-50. PubMed.