6 June 2008. 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.
Wikoff WR, Pendyala G, Siuzdak G, Fox HS. Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques.
J Clin Invest. 2008 Jun 2. [Epub ahead of print] Abstract