Amino Acid Clocks ALS Progression?

Amyotrophic lateral sclerosis (ALS) has joined the growing list of neurodegenerative diseases characterized by fluctuations in the amino acid N-acetylaspartate (NAA)—but with a twist. While the amino acid is known to drop in the brains of people with dementia, the authors of a study in the October Archives of Neurology report that it rises in the serum of people with ALS, especially those who deteriorate quickly. “The correlation between serum NAA level and disease progression rate suggests that it may be a useful biomarker of ALS,” wrote the authors, who were led by Isabella Simone at the University of Bari, Italy.

NAA is a well-known marker for healthy, functioning neurons. To examine the amino acid in ALS, the researchers collected serum samples from 112 people with sporadic ALS and 51 controls matched for age and gender. They used liquid chromatography and magnetic resonance spectroscopy to analyze the serum for NAA. Among people with ALS, NAA concentrations averaged 0.184 millimolar, compared to 0.86 millimolar in the healthy participants. To model the potential use of NAA as a biomarker, the researchers looked at the data across all subjects and set a cutoff of 0.171 millimolar, the median concentration. They calculated that people whose NAA levels fell above that median were nearly 20 times more likely to have ALS than those who came in under the cutoff. And people with ALS who had the highest serum NAA had the fastest-progressing disease.

“It is an exciting finding that there is a [serum] biomarker for possible changes in neuronal integrity,” said Kejal Kantarci of the Mayo Clinic in Rochester, Minnesota, who was not involved in the work. But this is only a first step, Kantarci noted. She would like to see a longitudinal study to test if serum NAA levels continue to rise as a person’s ALS progresses, compared to healthy controls.

Jeffrey Rothstein of Johns Hopkins University in Baltimore, Maryland, raised another issue: “I am not sure this is really unique to ALS,” he said. For example, serum NAA is high in people with multiple sclerosis (Tortorella et al., 2011). The researchers did not measure serum NAA in people with other, similar diseases.

Indeed, NAA appears to be a fairly broad-ranging marker. Kantarci and others have used magnetic resonance spectroscopy with brain imaging to observe that NAA levels are low in the brains of people with Alzheimer’s disease, vascular dementia, and frontotemporal dementia (reviewed in Kantarci, 2007), Parkinson’s disease with dementia (Griffith et al., 2008), and Huntington’s disease (Sturrock et al., 2010). Rothstein’s team has shown that NAA is decreased in the ventral horn, dorsal horn, and ventral column of people with ALS (Tsai et al., 1991). Nevertheless, the amino acid could prove a marker of progression rate in people already diagnosed with the disease, the authors say.

How does NAA wind up in the serum? If neurons are sick and release NAA, astrocytes might take up the amino acid and transfer it to the circulatory system, the authors hypothesize.—Amber Dance

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References

Paper Citations

  1. Tortorella C, Ruggieri M, Di Monte E, Ceci E, Iaffaldano P, Direnzo V, Mastrapasqua M, Frigeri A, Amato MP, Hakiki B, Ghezzi A, Lugaresi A, De Luca G, Patti F, D'amico E, Sola P, Simone AM, Svelto M, Livrea P, Trojano M. Serum and CSF N-acetyl aspartate levels differ in multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry. 2011 Dec;82(12):1355-9. PubMed.
  2. Kantarci K. 1H magnetic resonance spectroscopy in dementia. Br J Radiol. 2007 Dec;80 Spec No 2:S146-52. PubMed.
  3. Griffith HR, den Hollander JA, Okonkwo OC, O'brien T, Watts RL, Marson DC. Brain N-acetylaspartate is reduced in Parkinson disease with dementia. Alzheimer Dis Assoc Disord. 2008 Jan-Mar;22(1):54-60. PubMed.
  5. Tsai GC, Stauch-Slusher B, Sim L, Hedreen JC, Rothstein JD, Kuncl R, Coyle JT. Reductions in acidic amino acids and N-acetylaspartylglutamate in amyotrophic lateral sclerosis CNS. Brain Res. 1991 Aug 9;556(1):151-6. PubMed.

Further Reading

Papers

  1. Sarac H, Zagar M, Vranjes D, Henigsberg N, Bilić E, Pavlisa G. Magnetic resonance imaging and magnetic resonance spectroscopy in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. Coll Antropol. 2008 Jan;32 Suppl 1:205-10. PubMed.
  2. Han J, Ma L. Study of the features of proton MR spectroscopy ((1)H-MRS) on amyotrophic lateral sclerosis. J Magn Reson Imaging. 2010 Feb;31(2):305-8. PubMed.
  3. Lombardo F, Frijia F, Bongioanni P, Canapicchi R, Minichilli F, Bianchi F, Hlavata H, Rossi B, Montanaro D. Diffusion tensor MRI and MR spectroscopy in long lasting upper motor neuron involvement in amyotrophic lateral sclerosis. Arch Ital Biol. 2009 Sep;147(3):69-82. PubMed.
  4. Pioro EP, Antel JP, Cashman NR, Arnold DL. Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology. 1994 Oct;44(10):1933-8. PubMed.
  5. Rule RR, Suhy J, Schuff N, Gelinas DF, Miller RG, Weiner MW. Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Sep;5(3):141-9. PubMed.
  6. Kalra S, Hanstock CC, Martin WR, Allen PS, Johnston WS. Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Arch Neurol. 2006 Aug;63(8):1144-8. PubMed.

Primary Papers

  1. Simone IL, Ruggieri M, Tortelli R, Ceci E, D'Errico E, Leo A, Zoccolella S, Mastrapasqua M, Capozzo R, Livrea P, Logroscino G. Serum N-acetylaspartate level in amyotrophic lateral sclerosis. Arch Neurol. 2011 Oct;68(10):1308-12. PubMed.

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