title: Polyamines: Predictive Biomarker for HIV-Associated Neurocognitive Disorders.
abstract: OBJECTIVE
  Spermidine/spermine-N1-acetytransferase (SSAT) is the key enzyme in the catabolism of polyamines that are involved in regulating NMDA functioning. Over expression of SSAT leads to abnormal metabolic cycling and may disrupt NMDA receptor signaling. In fact, the HIV protein Tat induces neurotoxicity involving polyamine/NMDA receptor interactions. Thus, we investigated abnormal polyamine cycling in HIV+ participants with varying degrees of HIV-associated neurocognitive disorders.
  
  
  METHODS
  Acetyl-polyamine (SSAT products) levels were assessed by HPLC in CSF from 99 HIV-infected participants (no cognitive impairment (NCI, n=25), asymptomatic neurocognitive impairment (ANI, n=25), mild cognitive and motor disorders (MCMD, n=24), and HIV-associated dementia (HAD, n=25)). Polyamine levels in brain tissues from a subset of participants (uninfected (n=3), NCI (n=3), and MNCD (n=3)) were also assessed. Human primary astrocytes expressing HIV Tat were assessed for levels of the SSAT activity.
  
  
  RESULTS
  Activation of the polyamine catabolic enzyme, SSAT increases polyamine flux in brain and CSF of HIV infected individuals with HIV-associated neurocognitive disorders. CSF levels of acetylated polyamine increase with the degree of HAND severity as indicated by significantly increased acetylpolyamine levels in HAD participants compared to NCI and ANI (p<0.0001) and between MCMD and NCI and ANI (p<0.0001).In vitrostudies suggest that the HIV protein Tat may be responsible in part for astrocyte-derived acetyl polyamine release.
  
  
  CONCLUSIONS
  Our data suggest that polyamine metabolism may play a pivotal role in the neurodegeneration process among HAND patients. Changes in polyamine flux may serve as a potential predictive diagnostic biomarker for different severities of HAND.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA.
authors.forename: Salim
authors.initials: S
authors.lastname: Merali
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Barrero
authors.affiliation: Department of Neurology, Johns Hopkins Memory and Alzheimer's Disease Treatment Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ned C
authors.initials: NC
authors.lastname: Sacktor
authors.affiliation: Department of Neurology, Richard T Johnson Division of Neuroimmunology and Neurological Infections, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Datta
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
authors.affiliation: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
keywords: AIDS; Central nervous system; HIV associated neurocognitive disorders; HIV-1; Polyamines