Many researchers studying neurodegenerative disease focus their studies, naturally enough, on the affected organs of the nervous system. But in doing so, they may be ignoring a more accessible place to find the answers they seek, said Eugenia Wang of the University of Louisville in Kentucky. Peripheral blood, despite being separated from the central nervous system by the blood-brain barrier, nonetheless carries the “footprint” of the brain and spinal cord, she said. Scientists such as Wang have found changes in blood transcriptional profiles in people with Alzheimer disease (Maes et al., 2006). Now, researchers have taken the same line of inquiry in people with amyotrophic lateral sclerosis (ALS). In a paper published online on August 27 in BMC Genomics, researchers from the University of California in Los Angeles and the University Medical Center in Utrecht, The Netherlands, report that expression of 2,300 genes goes up or down in people with ALS.

“There’s actually a huge signal in blood,” said UCLA’s Steve Horvath, who is the statistician on the project. In addition to Horvath, Christian Saris and Paul van Vught from Utrecht were joint first authors; Horvath was also a principal investigator along with Leonard van den Berg from Utrecht and Roel Ophoff, who holds appointments at both institutions.

The researchers analyzed peripheral blood messenger RNA from three separate small cohorts, totaling 123 people newly diagnosed with ALS and an equal number of control subjects. Genes more highly expressed in people with ALS included those linked to post-translational modification and infection. Downregulated genes included those involved in genetic disorders, inflammatory disease, and skeletal and muscular disorders. Genes related to neurological disorders were well-represented at high levels in both the up- and downregulated categories.

Going by the gene expression data alone, the researchers were able to correctly classify 80 percent of participants as ALS or control. The remaining 20 percent were primarily false negatives, Horvath said, noting that some patients diagnosed as having ALS looked virtually indistinguishable from healthy controls. However, he added that a clinician hardly needs a blood test to distinguish a healthy person from one with ALS. Rather, the value of this approach could be in separating cases of ALS from disorders with similar presentation. His colleagues are planning a blood gene expression analysis with conditions that mimic ALS. In the longer run, data such as these may provide clues for basic researchers and ultimately for treatment development, said Wang, who was not involved in the study.

In the work done so far, the researchers were unable to link gene expression to other characteristics of disease, such as survival time. “It would have been nice,” Horvath said. “I wish we could have a smoking gun…. It remains a complex disease.”—Amber Dance.

Reference:
Saris CG, Horvath S, van Vught PW, van Es MA, Blauw HM, Fuller TF, Langfelder P, Deyoung J, Wokke JH, Veldink JH, van den Berg LH, Ophoff RA. Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients. BMC Genomics. 2009 Aug 27;10(1):405. Abstract

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References

Paper Citations

  1. . Transcriptional profiling of Alzheimer blood mononuclear cells by microarray. Neurobiol Aging. 2007 Dec;28(12):1795-809. PubMed.
  2. . Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients. BMC Genomics. 2009;10:405. PubMed.

Further Reading

Papers

  1. . Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol. 2009 Jan;117(1):55-62. PubMed.
  2. . Protein biomarkers for amyotrophic lateral sclerosis. Expert Rev Proteomics. 2008 Apr;5(2):249-62. PubMed.
  3. . Biomarkers for amyotrophic lateral sclerosis. Expert Rev Mol Diagn. 2006 May;6(3):387-98. PubMed.
  4. . Biomarkers of neurodegenerative disorders: how good are they?. Cell Res. 2004 Oct;14(5):347-58. PubMed.
  5. . Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients. BMC Genomics. 2009;10:405. PubMed.
  6. . Expression and polymorphisms of gene 8-oxoguanine glycosylase 1 and the level of oxidative DNA damage in peripheral blood lymphocytes of patients with Alzheimer's disease. DNA Cell Biol. 2009 Nov;28(11):579-88. PubMed.
  7. . Immune blood biomarkers of Alzheimer disease patients. J Neuroimmunol. 2009 May 29;210(1-2):67-72. PubMed.
  8. . A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis. Neurology. 2009 Jan 6;72(1):14-9. PubMed.
  9. . Elevated serum angiogenin levels in ALS. Neurology. 2006 Nov 28;67(10):1833-6. PubMed.
  10. . Plasma and cerebrospinal fluid-based protein biomarkers for motor neuron disease. Mol Diagn Ther. 2006;10(5):281-92. PubMed.

Primary Papers

  1. . Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients. BMC Genomics. 2009;10:405. PubMed.