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Surrogate Markers Core

Norman HaugheyDr. Norman Haughey, Core Director

Core Mission

Neurocognitive impairment in HIV-infected individuals remains a significant problem despite antiretroviral therapy. There is a critical need for surrogate markers that can be used to predict cognitive impairment and to monitor the effects of antiretroviral, or neuroprotective therapy in HIV-infected individuals.

Goals and Objectives

  • Assist in the development and monitoring of surrogate markers for HIV-associated neurocognitive disorders (HAND)
  • To provide mentorship and consultation for Neuro-AIDS researchers in the development of clinically useful surrogate markers for HAND and to validate these as predictive and associative markers for cognitive impairment and as surrogate markers for therapeutic effectiveness
  • Assist in the development of small molecule therapeutics by providing consultation on pharamcokinetic/pharmacodynamic considerations for drug development, and conducting pharmacokinetic and analysis of potential drugs and drug metabolites.

Recent Publications (2014-2015)

  • Bora, A., Mohien, CU., Chaerkady, R., Chang, L., Moxley, R., Sacktor, N., Haughey, NJ., McArthur, JC., Nath, A., and Graham, D.R.  Identification of putative biomarkers for HIV-associated neurocognitive impairment in the CSF of HIV-infected patients under cART therapy determined by mass spectrometry.  Journal of Neuroviology. 2014. 20(5):457-465
  • Bae, M., Bandaru, VVR., Patel, N., Xu, H., Lee, M., Tominaga-Yamanaka, K., Nath, A., Geiger, JD., Gorospe, M., Mattson, MP., Haughey, NJ. Activation of TRPML1 clears intraneuronal Ab in pre-clinical models of HIV-infection. J Neurosci. 2014. 34(34):11485-51103.
  • Bandaru, VVR., Haughey, NJ. Quantitative detection of free 24S-hydroxycholesterol and 27-hydroxycholesterol from human serum. 2014. BMC Neuroscience. 24;15(1):2.
  • Steiner JP, Bachani M, Wolfson-Stofko B, Lee MH, Wang T, Li G, Li W, Strayer D, Haughey NJ, Nath A. Interaction of Paroxetine with mitochondrial proteins mediates neuroprotection.  Neurotherapeutics. 2014. PLoS One. 26;9(12):e115642.
  • Sacktor, N., Miyahara, S., Evans, S., Schifitto, G., Cohen, B., Haughey, N.J., Drewes, JL., Graham, D., Zink, MC., Anderson, C., Nath, A., Pardo, C., McCarthy, S., Hosey, L., Clifford, D., on behalf of the ACTG A5235 team. Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV seropositive individuals with cognitive impairment. J. Neurovirol. 2014.  20(6):620-626.
  • Dickens AM, Anthony DC, Deutsch R, Mielke MM, Claridge TD, Grant I, Franklin D, Rosario D, Marcotte T, Letendre S, McArthur JC, Haughey NJ. Cerebral spinal fluid metabolomics implicate bioenergeic adaptation as a neural mechanism regulating shifts in cognitive states of HIV infected patients. 2015. AIDS. 13;29(5):559-569.

Highlighted Publications

Publication: Cerebral spinal fluid metabolomics implicate bioenergeic adaptation as a neural mechanism regulating shifts in cognitive states of HIV infected patients

CSF Metabolites

OBJECTIVES: To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients.
DESIGN: Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV-infected patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening.
METHODS: The metabolic composition of CSF was analysed using 1H nuclear magnetic resonance (1H NMR) spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features.
RESULTS: Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92%, sensitivity of 88% and 96% specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, [beta]-glucose and creatinine to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%.
CONCLUSION: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.

Fig. 4. Summary diagram demonstrating the key CSF metabolite changes found to occur during worsening (highlighted in red) and improving (highlighted in blue) cognitive status.ADP, adenosine diphosphate; ATP, adenosine triphosphate; CrP, creatine phosphate.

Publication: Quantitative detection of free 24S-hydroxycholesterol, and 27-hydroxycholesterol from human serum

Figure 3 chromo

BACKGROUND: Cholesterol metabolism is important for the maintenance of myelin and neuronal membranes in the central nervous system. Blood concentrations of the brain specific cholesterol metabolite 24S-hydroxysterol to the peripheral metabolite 27-hydroxycholesterol may be useful surrogate markers for neurodegenerative diseases including Alzheimer's disease, Huntington's disease, HIV-Associated Neurocognitive Disorders, and Multiple Sclerosis. However, current methods to isolate hydroxycholesterols are labor intensive, prone to produce variable extraction efficiencies and do not discriminate between free and esterfied forms of hydroxycholesterols. Since free hydroxycholesterols are the biologically active form of these sterols, separating free from esterfied forms may provide a sensitive measure to identify disease-associated differences in brain sterol metabolism.
RESULTS: We found that average human serum concentrations were 12.3 ± 4.79 ng/ml for free 24(s)-hydroxycholesterol and 17.7 ± 8.5 ng/ml for 27-hydroxycholesterol.
CONCLUSION: Serum measurements of these biologically active oxysterols may be useful surrogate measures for brain health in a variety of neurodegenerative conditions.

Figure 3 Chromatograms for 24S-hydroxycholesterol and 27-hydroxycholesterol. LC/MS/MS chromatograms for A) 24S-hydroxycholesterol and 27-hydroxycholesterol and B) 24(R/S)-hydroxycholesterol (d6). Base line chromatogram for C) methanol. D) Chromatogram for 24S-hydroxycholesterol (10.45) and 27-hydroxycholesterol (10.83) extracted from serumE) Chromatogram for 24S-hydroxycholesterol and 27-hydroxycholesterols spiked serum sample. F) Chromatogram of 24(R/S)-hydroxycholesterol (d6) added into and extracted from serum sample.

Team Members

Norman Haughey, Ph.D. (Core Director)
Carlos Pardo-Villamizar, M.D. (Co-Investigator)
David Graham, Ph.D. (Co-Investigator)
Alex Dickens, D.Phil. (Post-doctoral Fellow)
Joelle Dorskind (Research Assistant)
Jacqueline Lovett (Technician)

Collaborators

Michelle Mielke, Ph.D. (Mayo Clinic)
Reena Deutsch, Ph.D. (UCSD)

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