The introduction of combination antiretroviral therapy (cART) has resulted in a dramatic improvement in the life-expectancy for people living with HIV-infection. Although AIDS-defining illnesses such as HIV-dementia are now rare, mild cognitive disorders are still prevalent in a substantial proportion of patients on effective cART and suppressed HIV plasma viraemia. Although some clinic risk factors for HIV-associated neurocognitive impairment (NCI) such as low nadir CD4 T-cell count and age have been described, the pathological processes underlying this cognitive impairment remain elusive. A major factor that might be contributing to the development of HIV-associated NCI is chronic activation of macrophages and astrocytes resident in the brain microglia. I hypothesise that in vivo microglial activation is both present in effectively treated HIV-infected individuals and is associated with disturbances in cognitive function and biomarkers of magnetic resonance imaging (functional, structural and chemical) and inflammation To address these hypotheses I used cerebral positron emission tomography with [11C] PBR28 to measure translocator protein 18kDa (TSPO), a putative marker for microglial activation. To examine the impact of inflammation on brain structure, function and chemistry, neurologically asymptomatic HIV-infected individuals stable on cART were evaluated using several magnetic resonance imaging methods, cognitive testing and measurements of inflammatory biomarker in plasma and cerebrospinal fluid. I identified the presence of in vivo microglial activation in several brain regions in HIV-infected individuals compared to HIV-negative controls. Microglial activation was associated with disturbances in cognitive function (verbal and learning memory), brain activation (reduced task-related brain activation) and white matter integrity (increased mean diffusivity), suggesting a deleterious effect of neuroinflammation on brain structure and function. Microglial activation, across several anatomical locations correlated with increased concentrations of plasma ribosomal 16s, a marker of microbial translocation. This relationship between a marker of impaired integrity of the gut-blood barrier, and microglial activation, suggests a communication route is present between peripheral inflammation and the CNS in HIV-infected individuals. In vivo detection of microglial activation, and systemic inflammatory markers could provide indices to guide risk assessment and treatments for HIV-associated brain disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:666488 |
| Date | January 2014 |
| Creators | Vera Rojas, Jaime Vera |
| Contributors | Winston, Alan; Matthews, Paul |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/25988 |
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