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Probing Brain Physiology in Early and Acute HIV Infection (AEH) Using Quantitative Functional Magnetic Resonance Imaging (qfMRI)

Beau M. Ances, M.D., Ph.D., M.Sc.

Washington University
Funded in December, 2007: $100000 for 3 years
LAY SUMMARY . ABSTRACT . SELECTED PUBLICATIONS .

LAY SUMMARY

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A New Imaging Technique May Reveal Effects of HIV in the Brain, and of Therapies to Treat It

Investigators will determine the feasibility of combining two conventional brain imaging techniques in patients with HIV infection to help reveal how early and acute HIV infection affects the brain and how combination anti-retroviral therapies modify these effects.

HIV infection in the brain, which can occur even before HIV is clinically diagnosed, produces dementia. Yet at the earliest stages of brain HIV infection, the virus may be the most responsive to anti-retroviral therapies. Early detection of HIV in the brain (and the effects of therapies) cannot currently be imaged in the brain. Instead, diagnosis is made by analyzing cerebral spinal fluid. Two imaging techniques used simultaneously, however, may identify the physiologic effects of HIV in the brain. Specifically, HIV crosses the blood-brain-barrier through infected immune cells, called “macrophages,” and “microglia.” Immediately thereafter, these virus-infected immune molecules release viral proteins, cytokines, and chemokines.  They stimulate excessive release of the excitatory neurotransmitter glutamate from neurons, impair the removal of the excess glutamate by cells (called “astrocytes,”) and disrupt surrounding blood vessels. The brain responds by raising cerebral oxidative metabolism, which signals a rise in cerebral blood flow.

The researchers will determine the feasibility of simultaneously using BOLD fMRI and Arterial Spin Labeling (ASL) imaging to obtain a greater understanding of HIV-associated neurocognitive impairment and the effects of antiretroviral therapy on this process.  They will test this combined imaging approach, called quantitative fMRI, in 30 patients with early HIV, one-half of whom are taking antiretroviral therapy and one-half of whom have declined therapy, and in 15 matched healthy volunteers. The investigators will assess the technique’s feasibility in determining whether antiretroviral therapy fundamentaly alters the immune system’s reaction to HIV in the brain.

Significance: If this combined imaging technique is demonstrated to feasibly explore immune responses to HIV in the brain, and to HIV therapies, the techniques can be used to answer specific clinical questions. In the long-term, the technique may be able to successfully predict which patients with early HIV brain infection will have a beneficial response to therapy.

ABSTRACT

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Probing Brain Physiology in Early and Acute HIV Infection (AEH) Using Quantitative Functional Magnetic Resonance Imaging (qfMRI)

Soon after initial HIV infection, high levels of the virus disseminate throughout the body and cross the blood brain barrier. While sequestered in the brain, HIV continues to evolve in this protected reservoir. This application will utilize novel neuroimaging techniques to non-invasively examine the early pathogenic effects of HIV in the brain.

The proposed research project will study both cross sectionally and longitudinally a cohort of 30 HIV seropositive (HIV+) patients. This group will consist of acute and early HIV (AEH) infected ( < 1 year after seroconversion) (n=15) and chronic HIV infected (CH) (n=15) (> 1 year after seroconversion) subjects. Age, sex, and education matched seronegative controls (n=15) will serve as a comparison group. Experiments will use a recently developed quantitative functional magnetic resonance imaging (qfMRI) technique to characterize functional changes in cerebral blood flow (CBF) and oxygen metabolism (CMRO2) to a standard stimulus. Within the HIV group initiation of combination anti-retroviral therapy (cART) could alter the immune system’s reaction to HIV in the brain as detected by qfMRI measures. In a subset of the HIV cohort starting cART we will longitudinally perform qfMRI both prior to and 6 months after these individuals initiate medications.

This proposal will test the following hypotheses: 1) Functional changes in CBF and CMRO2 correlate with length of infection. Both AEH and CH subjects have higher functional changes in CBF and CMRO2 compared to seronegative controls. Soon after HIV infection an upregulation of glutamatergic transmission demands may lead to increases in observed qfMRI measures.  2) The impact of initiation of cART may be dependent on the length of infection as measured by qfMRI measures.

Early initiation of cART in AEH subjects will fundamentally alter the immune system’s reaction to HIV in the brain. A greater normalization in both the CBF and CMRO2 responses will be observed within AEH individuals starting cART compared to those declining therapy.

Early detection of the pathogenic effects of HIV in the brain is crucial for determining the optimal time for commencing treatment.  qfMRI could be a sensitive biomarker of HIV related brain pathology and may therefore play an important role in novel therapeutic decisions.

SELECTED PUBLICATIONS

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Ances B.M., Vaida F., Rosario D., Marquie-Beck J., Ellis R.J., Simpson D.M., Clifford D.B., McArthur J.C., Grant I., McCutchan J.A., CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Metabolic Study Group. AIDS. 2009 November 13; Role of Metabolic Syndrome Components in HIV Associated Sensory Neuropathy. NIH Public Access; Author Manuscript.

Ances B.M., 2011 November 30; The more things change the more they stay the same: a case report of neurology residency experiences. J Neurology.

Ances B.M., Ortega M., Vaida F., Heaps J., Paul R., 2012 February 4; Independent Effects of HIV, Aging, and HAART on Brain Volumetric Measures. AIDS 2012.

Roc A.C., Ances B.M., Chawla S., Korczykowski M., Wolf R.L., Kolson D.L., Detre J.A., Poptani H., 2007 July 9; Detection of Human Immunodeficiency Virus–Induced Inflammation and Oxidative Stress in Lenticular Nuclei With Magnetic Resonance Spectroscopy Despite Antiretroviral Therapy. Archives of Neurology.

Ances B.M., Liang C.L., Leontiev O., Perthen J.E., Fleisher A.S., Lansing A.E., Buxton R.B., 2009 April 30; Effects of Aging on Cerebral Blood Flow, Oxygen Metabolism, and Blood Oxygenation Level Dependent Responses to Visual Stimulation. Human Brain Mapping. NIH Public Access; Author Manuscript.

Ances B.M., Vaida F., Cherner M., Yeh M.J., Liang C.L., Gardener C., Grant I., Ellis R.J., Buxton R.B., HIV Neurobehavioral Research Center Group, 2011 March 24;  HIV and Chronic Methamphetamine Dependence Affect Cerebral Blood Flow. J Neuroimmune Pharmacol.

Ances B.M., Bhatt A., Vaida F., Rosario D., Alexander T., Marquie-Beck J., Ellis R.J., Letendre S., Grant I., McCutchan J.A., HIV Neurobehavioral Research Center Group, 2010 July 3; Role of metabolic syndrome components in human immunodeficiency virus–associated stroke. NIH Public Access; Author Manuscript. J Neurovirology.

Ances B.M., Vaida F., Yeh M.J., Liang C.L., Buxton R.B., Letendre S., McCutchan J.A., Ellis R.J., HIV Neurobehavioral Research, 2011 February 1; HIV and Aging Independently Affect Brain Function as Measured by Functional Magnetic Resonance Imaging.

Ances B.M., Leontiev O., Perthen J.E., Liang C., Lansing A.E., Buxton R.B., 2010 February 10; Regional differences in the coupling of cerebral blood flow and oxygen metabolism changes in response to activation: Implications for BOLD-fMRI. NIH Public Access; Author Manuscript

Ances B.M., Sisti D., Vaida F., Liang C.L., Leontiev O., Perthen J.E., Buxton R.B., Benson D., Smith D.M., Little S.J., Richman D.D., Moore D.J., Ellis R.J., HNRC Group, 2009; Resting cerebral blood flow; A potential biomarker of the effects of HIV in the brain. Neurology.

Ances B.M., Christensen J.J., Teshome M., Taylor J., Xiong C., Aldea P., Fagan A.M., Holtzman D.M., Morris J.C., Mintun M.A., Clifford D.B., 2010; Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB; A case-control study. Neurology.

Ances B.M., Vaida F., Ellis R., Buxton R.B., 13 October 2012; Test–retest stability of calibrated BOLD-fMRI in HIV− and HIV+ subjects. NeuroImage.

Grantee Q&A: Mark Wooten

More than 30,000 people in the US contract Lyme disease each year; the inflammatory disorder can lead to long-term complications with the skin, heart, joints, and brain. We talk to Dana grantee Mark Wooten about his research into how the causal bacterium, Borrelia burgdorferi, can become almost invisible to the mammalian immune system after infection, making the disease difficult to diagnose and treat.


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