Neuroinflammation is a major component of several neurodegenerative disorders such as
Alzheimers disease, HIV-associated dementia, Multiple sclerosis and Parkinsons disease.
Although the primary pathology underlying each of these diseases is vastly different,
neuroinflammation, consisting of chronic activation of brain macrophages, is a significant factor
that contributes to neuronal damage in all these conditions. Were it possible to image chronic
activation of brain macrophages, it would be possible to monitor developing neuroinflammation
and assess the efficacy of therapies that are targeted at modulating CNS inflammation.
The goal of this thesis is to determine if activated brain macrophages can be imaged in
vivo using positron emission tomography. We propose to take advantage of increased expression
of the peripheral benzodiazepine receptor in activated brain macrophages and hypothesize that
ligands that bind specifically to this receptor will label activated brain macrophages in vivo
using positron emission tomography. The peripheral benzodiazepine receptor is normally
expressed at low levels in the central nervous system in astrocytes and brain macrophages and is
hypothesized to increase specifically on brain macrophages in neuroinflammation.
We show that PK11195, a specific ligand to the peripheral benzodiazepine receptor,
shows increased binding to brain macrophages in HIV encephalitis and that PK11195 can be
used to image brain macrophages in vivo using positron emission tomography in a macaque
model of HIV encephalitis. PK11195 binding is also increased in activated brain macrophages in
Alzheimers disease and shows age dependent increases in transgenic mice models of
Alzheimers disease. Finally we compare binding characteristics of DAA1106, a novel
peripheral benzodiazepine receptor ligand, with PK11195 to show that DAA1106 binds with
greater affinity in rat models of neuroinflammation both in brain tissues as well as in vivo. These
data suggest that ligands of the peripheral benzodiazepine receptor specifically label activated
brain macrophages and may be used to image neuroinflammation in vivo using positron emission
tomography.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04282006-185724 |
| Date | 28 June 2006 |
| Creators | Venneti, Sriram |
| Contributors | Donald DeFranco, Clayton A. Wiley, Charleen T. Chu, Patrick J. Card, Michael J. Zigmond, Eliezer Masliah |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04282006-185724/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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