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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    • "In summary, some neuroimaging studies of HIV-infection have shown abnormal hyperactivation in the association cortices and others have found aberrant hypoactivation in modality-specific regions, but no studies have demonstrated both patterns of activation in the same group of HIV-infected patients. Likewise, some sMRI investigations have found gray matter reductions to be much more severe in the primary sensory regions of HIV-infected patients [Thompson et al., 2005], whereas others have found structural abnormalities to be more widespread in association cortices [Cardenas et al., 2009]. "
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    ABSTRACT: Combination antiretroviral therapy transformed human immunodeficiency virus (HIV)-infection from a terminal illness to a manageable condition, but these patients remain at a significantly elevated risk of developing cognitive impairments and the mechanisms are not understood. Some previous neuroimaging studies have found hyperactivation in frontoparietal networks of HIV-infected patients, whereas others reported aberrations restricted to sensory cortices. In this study, we utilize high-resolution structural and neurophysiological imaging to determine whether alterations in brain structure, function, or both contribute to HIV-related cognitive impairments. HIV-infected adults and individually matched controls completed 3-Tesla structural magnetic resonance imaging (sMRI) and a mechanoreception task during magnetoencephalography (MEG). MEG data were examined using advanced beamforming methods, and sMRI data were analyzed using the latest voxel-based morphometry methods with DARTEL. We found significantly reduced theta responses in the postcentral gyrus and increased alpha activity in the prefrontal cortices of HIV-infected patients compared with controls. Patients also had reduced gray matter volume in the postcentral gyrus, parahippocampal gyrus, and other regions. Importantly, reduced gray matter volume in the left postcentral gyrus was spatially coincident with abnormal MEG responses in HIV-infected patients. Finally, left prefrontal and postcentral gyrus activity was correlated with neuropsychological performance and, when used in conjunction, these two MEG findings had a sensitivity and specificity of over 87.5% for HIV-associated cognitive impairment. This study is the first to demonstrate abnormally increased activity in association cortices with simultaneously decreased activity in sensory areas. These MEG findings had excellent sensitivity and specificity for HIV-associated cognitive impairment, and may hold promise as a potential disease marker.
    Human Brain Mapping 11/2014; 36(3). DOI:10.1002/hbm.22674 · 5.97 Impact Factor
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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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    ABSTRACT: Cognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV + patients scanned with whole-brain MRI at 1.5 T (mean age: 48.6 ± 8.4 years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4 + count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4 +. Even so, brain volume measured by TBM showed no detectable association with current CD4 + count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage.
    Clinical neuroimaging 12/2013; 3:132–142. DOI:10.1016/j.nicl.2013.07.009 · 2.53 Impact Factor
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    • "Previous clinical studies reported that cognitive impairment in HIV-infected individuals can occur in the context of maximal viral suppression in the serum [30]–[33]. Some of these studies showed a correlation between cognitive deficits and age [31], [32]. "
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    ABSTRACT: Mild neurocognitive disorders (MND) affect a subset of HIV+ patients under effective combination antiretroviral therapy (cART). In this study, we used an innovative multi-contrast magnetic resonance imaging (MRI) approach at high-field to assess the presence of micro-structural brain alterations in MND+ patients. We enrolled 17 MND+ and 19 MND- patients with undetectable HIV-1 RNA and 19 healthy controls (HC). MRI acquisitions at 3T included: MP2RAGE for T1 relaxation times, Magnetization Transfer (MT), T2* and Susceptibility Weighted Imaging (SWI) to probe micro-structural integrity and iron deposition in the brain. Statistical analysis used permutation-based tests and correction for family-wise error rate. Multiple regression analysis was performed between MRI data and (i) neuropsychological results (ii) HIV infection characteristics. A linear discriminant analysis (LDA) based on MRI data was performed between MND+ and MND- patients and cross-validated with a leave-one-out test. Our data revealed loss of structural integrity and micro-oedema in MND+ compared to HC in the global white and cortical gray matter, as well as in the thalamus and basal ganglia. Multiple regression analysis showed a significant influence of sub-cortical nuclei alterations on the executive index of MND+ patients (p = 0.04 he and R(2) = 95.2). The LDA distinguished MND+ and MND- patients with a classification quality of 73% after cross-validation. Our study shows micro-structural brain tissue alterations in MND+ patients under effective therapy and suggests that multi-contrast MRI at high field is a powerful approach to discriminate between HIV+ patients on cART with and without mild neurocognitive deficits.
    PLoS ONE 09/2013; 8(9):e72547. DOI:10.1371/journal.pone.0072547 · 3.23 Impact Factor
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