Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol

University of California, Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
Journal of NeuroVirology (Impact Factor: 2.6). 06/2009; 15(4):324-33. DOI: 10.1080/13550280902973960
Source: PubMed


Treatment with antiretroviral therapy (ART) has greatly reduced the incidence of dementia. The goal of this longitudinal study was to determine if there are ongoing macrostructural brain changes in human immunodeficiency virus-positive (HIV + ) individuals treated with ART. To quantify brain structure, three-dimensional T1-weighted magnetic resonance imaging (MRI) scans were performed at baseline and again after 24 months in 39 HIV+ patients on ART and 30 HIV- controls. Longitudinal changes in brain volume were measured using tissue segmentation within regions of interest and deformation morphometry. Measured by tissue segmentation, HIV+ patients on ART had significantly (all P<.05) greater rates of white matter volume loss than HIV- control individuals. Compared with controls, the subgroup of HIV+ individuals on ART with viral suppression also had significantly greater rates of white matter volume loss. Deformation morphometry confirmed these results with more specific spatial localization. Deformation morphometry also detected greater rates of gray matter and white matter loss in the subgroup of HIV+ individuals with detectable viral loads. These results provide evidence of ongoing brain volume loss in HIV+ individuals on stable ART, possibly suggesting ongoing cerebral injury. The presence of continuing injury raises the possibility that HIV+ individuals-even in the presence of viral suppression in the periphery-are at greater risk for future cognitive impairments and dementia and possibly faster cognitive decline. Therefore, HIV+ individuals on ART should be monitored for cognitive decline, and treatments that reduce ongoing neurological injury should be considered.

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Available from: Dieter Johannes Meyerhoff, Mar 25, 2014
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    ABSTRACT: Cell-free mitochondiral DNA (mtDNA) is an immunogenic molecule associated with many inflammatory conditions. We evaluated the relationship between cell-free mtDNA in cerebrospinal fluid (CSF) and neurocognitive performance and inflammation during HIV infection. In a cross-sectional analysis, we evaluated the association of mtDNA levels with clinical assessments, inflammatory markers, and neurocognitive performance in 28 HIV-infected individuals. In CSF, we measured mtDNA levels by droplet digital PCR, and soluble CD14 and CD163, neurofilament light, and neopterin by ELISA. In blood and CSF, we measured soluble IP-10, MCP-1, TNF-α, and IL-6 by ELISA, and intracellular expression of IL-2, IFN-γ, and TNF-α in CD4(+) and CD8(+) T cells by flow cytometry. We also evaluated the relationship between CSF pleocytosis and mtDNA longitudinally in another set of five individuals participating in an antiretroviral treatment (ART) interruption study. Cell-free CSF mtDNA levels strongly correlated with neurocognitive performance among individuals with neurocognitive impairment (NCI) (r = 0.77, p = 0.001). CSF mtDNA also correlated with levels of IP-10 in CSF (r = 0.70, p = 0.007) and MCP-1 in blood plasma (r = 0.66, p = 0.01) in individuals with NCI. There were no significant associations between inflammatory markers and mtDNA in subjects without NCI, and levels of mtDNA did not differ between subjects with and without NCI. MtDNA levels preceded pleocytosis and HIV RNA following ART interruption. Cell-free mtDNA in CSF was strongly associated with the severity of neurocognitive dysfunction and inflammation only in individuals with NCI. Our findings suggest that within a subset of subjects cell-free CSF mtDNA is associated with inflammation and degree of NCI.
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    • "Methamphetamine use may also cause hypertrophy of the white matter (perhaps due to inflammation); although the cause and consistency of the white matter effects of meth are not well-understood, some cohorts deliberately assess HIV participants with co-morbid IV drug use, where the balance of effects tends to reflect a combination of viral effects and those of chronic drug use. Recent evidence for white matter changes in HIV+ participants includes faster rates of white matter volume loss in HIV+ patients on stable cART with viral suppression (Cardenas et al., 2009), lower white matter fractional anisotropy as well as greater brain network deficits measured by diffusion tensor imaging (Chen et al., 2009; Jahanshad et al., 2012; Nir et al., 2013; Pfefferbaum et al., 2007; Pfefferbaum et al., 2009; Ragin et al., 2004; Tate et al., 2010; Wu et al., 2006). In the HIVNC cohort and a separate cohort named CNS HIV Antiretroviral Therapy Effects Research (CHARTER), nadir CD4 + count has been associated with lower total white matter and subcortical gray matter volumes (Cohen et al., 2010b; Jernigan et al., 2011), as well as lower corpus callosum volumes (Tate et al., 2011). "
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