A scan of cerebrospinal fluid from simian immunodeficiency virus (SIV)-infected monkeys turned up potential markers of central nervous system disease. The report, from Gary Siuzdak and Howard Fox of the Scripps Research Institute in La Jolla, California, shows the potential of metabolomics, a comprehensive cataloguing of small molecules, to yield biomarkers for CNS conditions, possibly including Alzheimer disease and other neurodegenerative disorders. The work appears in the June 2 online edition of the Journal of Clinical Investigation.

In humans, HIV infection of the CNS can lead to cognitive complications including dementia, but the pathophysiology of that damage is not well understood. In the current study, first author William Wikoff, along with Gurudutt Pendyala, Siuzdak, and Fox, used a monkey model of HIV infection to look for clues to the process. They performed a mass spectrometry analysis of CSF from four monkeys before infection, shortly after infection, and at sacrifice one to four months after infection. For the study, they chose monkeys with symptoms of CNS involvement.

Of 3,687 different components they identified in the CSF, 142 (4 percent) changed more than 1.5-fold after infection. Most of the metabolites that changed (97 percent) increased with infection. Eleven of these metabolites were identified as carnitines, acyl-carnitines, fatty acids, and phospholipids. The changes were markers of CNS infection, and not general SIV infection, because the same metabolites were not altered in infected animals without signs of CNS involvement.

The observed increase in fatty acids and phospholipids could be due to either pathological processes like phospholipase C activation, or to breakdown of the blood-brain barrier. Both factors may be at work, the results suggested. Measurements of mRNA for two phospholipases confirmed increased levels in the monkeys’ brains. In addition, all of the monkeys showed evidence of compromised blood-brain barrier.

In AD, CSF proteins have received the most attention as biomarkers so far. A decrease in Aβ peptides and an increase in phosphorylated tau indicate an increased risk of conversion to dementia (see ARF related news story). In the metabolite arena, Fox and colleagues cite two older papers indicating that neither carnitine nor acyl-carnitine levels in CSF correlate with AD (Rubio et al., 1998), and that a decrease—rather than an increase—in CSF fatty acids concentration was seen in AD (Mulder et al., 1998). Thus, changes in metabolomic profiles are likely distinct in different CNS diseases, and the authors conclude that, “Similar studies in other neurodegenerative as well as neuropsychiatric disorders have the potential to address the physiological disruptions underlying CNS diseases.”—Pat McCaffrey

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  1. In this study, Wikoff et al. utilized non-biased metabolomics approaches to investigate CSF metabolome changes in SIV-infected monkeys. The authors reported that the levels of several specific carnitines, fatty acids, and lysophosphatidylcholines were increased in the infected monkeys with encephalitis, possibly due to the upregulation of PLAs and the breakdown of BBB. This report is an exemplar of applying the methodology developed in Dr. Siuzdak’s lab (i.e., XCMS) to neuroscience. Certainly, the current study elegantly demonstrates the enormous potential of metabolomics for the discovery of novel biomarkers and pathogenic pathways in neurodegenerative disorders.

    However, the study also reveals the limitation of current technologies. Although hundreds of distinct features were observed, only 12 metabolites were identified and the identities of 11 metabolites were confirmed by using Q-TOF. To overcome such limitation, high resolution FT-MS/MS or high sensitivity capillary NMR studies are warranted to identify other unknown metabolites, which may lead to the discovery of novel biological pathways. In the future, approaches that couple genomics, proteomics, and metabolomics tools may enable us to understand the system from a holistic perspective, as opposed to the reductionist approach.

References

News Citations

  1. Biomarker Roundup: Collecting Clues from MRIs to RNAs

Paper Citations

  1. . Cerebrospinal fluid carnitine levels in patients with Alzheimer's disease. J Neurol Sci. 1998 Mar 5;155(2):192-5. PubMed.
  2. . Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis Assoc Disord. 1998 Sep;12(3):198-203. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques. J Clin Invest. 2008 Jun 2; PubMed.