White matter changes in HIV-1 infected brains: A combined gross anatomical and ultrastructural morphometric investigation of the corpus callosum

Wohlschlaeger, Jeremias; Wenger, Emanuel; Mehraein, P.; Weis, Serge

doi:10.1016/j.clineuro.2008.12.006

Cited by 29 publications

(36 citation statements)

References 56 publications

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“…To our knowledge, this is the largest study of the CC in treated HIV subjects and extends findings from previous studies demonstrating significant reductions in total CC area between controls and more clinically advanced HIV-infected subjects or in subjects with additional comorbid risk factors such as drug and alcohol abuse (Cardenas et al 2009; Chiang et al 2007; Pfefferbaum et al 2006; Thompson et al 2005, 2006; Wohlschlaeger et al 2009). A novel feature to our study was the utilization of 100 equidistant linear widths in addition to five regional divisions as previously described (Thompson et al 2006).…”

Section: Discussionsupporting

confidence: 81%

“…One recent pathological study (Wohlschlaeger et al 2009) found a significant decrease in CC area (~8%) in HIV-infected patients compared with controls that was associated with a global reduction in the absolute number of nerve fibers (~12%), with the most atrophy and reduction of nerve fibers occurring in the frontal and occipital regions of the CC (~28% in the anterior midbody and ~13% in the splenium). Moreover, the authors demonstrated alterations in the shape and caliber of axons that are also reflected in gross morphologic measures.…”

Section: Discussionmentioning

confidence: 99%

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Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies

et al. 2011

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Recent reports suggest that a growing number of human immunodeficiency virus (HIV)-infected persons show signs of persistent cognitive impairment even in the context of combination antiretroviral therapies (cART). The basis for this finding remains poorly understood as there are only a limited number of studies examining the relationship between CNS injury, measures of disease severity, and cognitive function in the setting of stable disease. This study examined the effects of HIV infection on cerebral white matter using quantitative morphometry of the midsagittal corpus callosum (CC) in 216 chronically infected participants from the multisite HIV Neuroimaging Consortium study currently receiving cART and 139 controls. All participants underwent MRI assessment, and HIV-infected subjects also underwent measures of cognitive function and disease severity. The midsagittal slice of the CC was quantified using two semi-automated procedures. Group comparisons were accomplished using ANOVA, and the relationship between CC morphometry and clinical covariates (current CD4, nadir CD4, plasma and CSF HIV RNA, duration of HIV infection, age, and ADC stage) was assessed using linear regression models. HIV-infected patients showed significant reductions in both the area and linear widths for several regions of the CC. Significant relationships were found with ADC stage and nadir CD4 cell count, but no other clinical variables. Despite effective treatment, significant and possibly irreversible structural loss of the white matter persists in the setting of chronic HIV disease. A history of advanced immune suppression is a strong predictor of this complication and suggests that antiretroviral intervention at earlier stages of infection may be warranted.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies

et al. 2011

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“…This observation supports previous findings of global callosal atrophy in the context of HIV infection [30], and both findings have recently been confirmed using postmortem morphometric analysis [31]. Local areas of abnormal signal intensity have also been observed in the CC [20] and have been linked to AIDS dementia complex severity [7].…”

Section: Structural Magnetic Resonance Imagingsupporting

confidence: 78%

The Role of Medical Imaging in Defining CNS Abnormalities Associated with HIV-Infection and Opportunistic Infections

et al. 2011

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Summary:In this review of the current literature, we examine the role of medical imaging in providing new and relevant information on central nervous system (CNS) injury associated with human immunodeficiency virus (HIV) infection and various clinical manifestations of this injury. Common imaging modalities used to examine CNS injury in HIV infection include structural magnetic resonance imaging, magnetic resonance spectroscopy, diffusion tensor imaging, functional MRI, and positron emissions tomography. Clinical implications for the findings are discussed for each of these modalities individually and collectively. In addition, the direction for future studies is suggested in an attempt to provide possible methods that might answer the many questions that remain to be answered on the evolution and progression of CNS injury in the context of HIV infection.

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“…The virus persistent in a latent or restricted manner in monocyte-macrophages, microglia and astrocytes continues to play a significant disease-inciting role. Indeed, HAND remains a subcortical dementia with notable evidence of affected white matter tracts within the corpus callosum, internal capsule and superior longitudinal fasciculus (Hoare et al, 2011; Sarma et al, 2014; Wohlschlaeger et al, 2009). How HIV-1 brain infection causes white matter damage is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…Up to half of infected individuals develop HIV-1-associated neurocognitive disorders (HAND), the cause(s) remain obscure. Many studies have revealed a preferential damage to cerebral white matter in HIV-1-infected brain (Gongvatana et al, 2009; Hoare et al, 2011; Sarma et al, 2014; Wohlschlaeger et al, 2009), and such damage is prevalent even in the era of cART and more severe in patients with HAND (Chen et al, 2009b; Gosztonyi et al, 1994). Structure magnetic resonance imaging and diffusion tensor imaging studies in HIV-1-infected individuals have revealed a subcortical white matter damage mainly in the regions of the corpus callosum, internal capsule and other brain regions (Chang et al, 2008; Chen et al, 2009b; Gongvatana et al, 2009; Pomara et al, 2001; Sarma et al, 2014; Wu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

Liu

et al. 2017

Neurobiology of Disease

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Brain white matter damage is frequently detected in patients infected with human immunodeficiency virus type 1 (HIV-1). White matter is composed of neuronal axons sheathed by oligodendrocytes (Ols), the myelin-forming cells in central nervous system. Ols are susceptible to HIV-1 viral trans-activator of transcription (Tat) and injury of Ols results in myelin sheath damage. It has been demonstrated that activation of voltage-gated K+ (KV) channels induces cell apoptosis and Ols predominantly express K+ channel KV1.3. It is our hypothesis that Tat injures Ols via activation of KV1.3. To test this hypothesis, we studied the involvement of KV1.3 in Tat-induced Ol/myelin injury both in vitro and ex vivo. Application of Tat to primary rat Ol cultures enhanced whole-cell KV1.3 current recorded under voltage clamp configuration and confirmed by specific KV1.3 antagonists Margatoxin (MgTx) and 5-(4-phenoxybutoxy) psoralen (PAP). The Tat enhancement of KV1.3 current was associated with Tat-induced Ol apoptosis, which was blocked by MgTx and PAP or by siRNA knockdown of KV1.3 gene. The Tat-induced Ol injury was validated in cultured rat brain slices, particularly in corpus callosum and striatum, that incubation of the slices with Tat resulted in myelin damage and reduction of myelin basic protein which were also blocked by aforementioned KV1.3 antagonists. Further studies revealed that Tat interacts with KV1.3 as determined by protein pull-down of recombinant GST-Tat with KV1.3 expressed in rat brains and HEK293 cells. Such protein-protein interaction may alter channel protein phosphorylation, resultant channel activity and consequent Ol/myelin injury. Taken together, these results demonstrate an involvement of KV1.3 in Tat- induced Ol/myelin injury, a potential mechanism for the pathogenesis of HIV-1-associated white matter damage.

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White matter changes in HIV-1 infected brains: A combined gross anatomical and ultrastructural morphometric investigation of the corpus callosum

Cited by 29 publications

References 56 publications

Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies

Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies

The Role of Medical Imaging in Defining CNS Abnormalities Associated with HIV-Infection and Opportunistic Infections

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

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