Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

Israel, Sarah M.; Hassanzadeh‐Behbahani, Shiva; Turkeltaub, Peter E.; Moore, David J.; Ellis, Ronald J.; Jiang, Xiong

doi:10.1002/hbm.24577

Cited by 37 publications

(34 citation statements)

References 92 publications

(172 reference statements)

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“…Other subcortical brain regions have also been implicated in selective vulnerability to HIV and associated NCI. Vulnerability of the neostriatum (caudate + putamen) to HIV-associated blood-brain barrier disruption and impaired function has been observed, especially in individuals with HIV-associated dementia and HIV-encephalitis (Berger and Arendt 2000;Chaganti et al 2019;Israel et al 2019;Lopez et al 1999;Melrose et al 2008;Meltzer et al 1998). Our study also implicates the globus pallidus, which, along with caudate and putamen, shows neuroinflammation (microglial activation) in PLWH despite a suppressive combination of antiretroviral therapy (Vera et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV

et al. 2020

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Previous studies showed that persons living with HIV (PLWH) demonstrate higher brain prefrontal cortex neuroinflammation and immunoproteasome expression compared to HIV-negative individuals; these associate positively with HIV levels. Lower expression of the antioxidant enzyme heme oxygenase 1 (HO-1) was observed in PLWH with HIV-associated neurocognitive impairment (HIV-NCI) compared to neurocognitively normal PLWH. We hypothesized that similar expression patterns occur throughout cortical, subcortical, and brainstem regions in PLWH, and that neuroinflammation and immunoproteasome expression associate with lower expression of neuronal markers. We analyzed autopsied brains (15 regions) from 9 PLWH without HIV-NCI and 7 matched HIV-negative individuals. Using Western blot and RT-qPCR, we quantified synaptic, inflammatory, immunoproteasome, endothelial, and antioxidant biomarkers, including HO-1 and its isoform heme oxygenase 2 (HO-2). In these PLWH without HIV-NCI, we observed higher expression of neuroinflammatory, endothelial, and immunoproteasome markers in multiple cortical and subcortical regions compared to HIV-negative individuals, suggesting a global brain inflammatory response to HIV. Several regions, including posterior cingulate cortex, globus pallidus, and cerebellum, showed a distinct pattern of higher type I interferon (IFN)-stimulated gene and immunoproteasome expression. PLWH without HIV-NCI also had (i) stable or higher HO-1 expression and positive associations between (ii) HO-1 and HIV levels (CSF, plasma) and (iii) HO-1 expression and neuroinflammation, in multiple cortical, subcortical, and brainstem regions. We observed no differences in synaptic marker expression, suggesting little, if any, associated neuronal injury. We speculate that this may reflect a neuroprotective effect of a concurrent HO-1 antioxidant response despite global neuroinflammation, which will require further investigation.

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Section: Discussionmentioning

confidence: 99%

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV

et al. 2020

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“…Neuroimaging is a promising approach to assess brain morphometric and functional changes that shows broad application prospects in the diagnosis and management of PLWH and may have the potential to shed light on the pathogenesis of HAND ( Clifford and Ances, 2013 ; Saylor et al, 2016 ; Campbell et al, 2019 ). Previous structural MRI studies indicated that PLWH display widespread brain atrophy in the subcortical nucleus as well as the frontal, parietal, occipital, temporal, and cerebellar cortices and cortical thinning in the frontal and temporal lobes and cingulate cortex ( Wilson et al, 2015 ; Underwood et al, 2017 ; Sanford et al, 2018a , b ; Israel et al, 2019 ; Hassanzadeh-Behbahani et al, 2020 ). Diffuse abnormalities in white matter (WM) microstructure were also noticed, including reduced fractional anisotropy with increased mean and radial diffusivity ( O’Connor et al, 2017 ; Underwood et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…The relationship between cognitive performance and neuroimaging is controversial. Whereas neuroimaging alterations in morphometry, diffusion, FC, and network topology were reported to be correlated with cognitive function ( Wilson et al, 2015 ; Underwood et al, 2017 ; Haddow et al, 2019 ; Israel et al, 2019 ; Kato et al, 2020 ), there are also studies that failed to find any such associations ( Thomas et al, 2013 ; Su et al, 2016 ; Wang et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Altered Gray Matter Volume and Functional Connectivity in Human Immunodeficiency Virus-Infected Adults

et al. 2020

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People living with human immunodeficiency virus (HIV) (PLWH) are at high risk of neurocognitive impairment. The pathogenesis of neurocognitive impairment remains unclear, and there is still no diagnostic biomarker. By coupling three-dimensional T1-weighted imaging and resting-state functional imaging, we explored structural and functional alterations in PLWH and examined whether such imaging alterations had the potential to denote neurocognitive function. A total of 98 PLWH and 47 seronegative controls aged 20–53 years were recruited. Structural alterations were first explored between HIV-negative controls and PLWH. Subsequently, brain regions showing gray matter alterations were used as seeds for separate whole-brain functional connectivity (FC) analysis. Finally, the relationships between imaging alterations and cognitive function were explored. PLWH suffered from thalamus, occipital lobe, and hippocampus/parahippocampus atrophy. Visual cortices in PLWH showed decreased anticorrelation with the posterior cingulate cortex and left angular gyrus of the default mode network. FC within the visual cortices (between the left calcarine and right calcarine) and in the thalamic prefrontal circuit and between the thalamus and somatosensory association cortex were also altered. In addition, FC between the left thalamus and right dorsolateral prefrontal cortex in the cognitively impaired group was significantly different from that in the cognitively normal group in PLWH. Partial correlation analysis uncorrected for multiple comparisons suggested that some imaging alterations can be associated with neurocognition. Our study supports the presence of brain atrophy and functional reconfiguration in PLWH. Imaging alterations can be associated with neurocognitive function. We hold that neuroimaging is a promising approach in evaluating PLWH and might have the potential to clarify the pathogenesis of HIV-associated neurocognitive disorder.

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“…ERβ, however, is involved in mediating estradiol signaling in the immune and central nervous systems (for review, Paterni et al 2014). Within the central nervous system, cells containing ERβ mRNA or immunoactivity are widely dispersed (e.g., Li et al 1997;Shughrue et al 1997;Zhang et al 2002;Gonzalez et al 2007), and observed in brain regions (e.g., prefrontal cortex, ventral tegmental area, hippocampus) commonly associated with HAND (e.g., Maki et al 2009;Israel et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Selective Estrogen Receptor β Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders

McLaurin

Moran

Booze

et al. 2019

J Neuroimmune Pharmacol

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The persistence of HIV-1 associated neurocognitive disorders (HAND) in the post-cART era, afflicting between 40 and 70% of HIV-1 seropositive individuals, supports a critical need for the development of adjunctive therapeutic treatments. Selective estrogen receptor β agonists, including S-Equol (SE), have been implicated as potential therapeutic targets for the treatment of neurocognitive disorders. In the present study, the therapeutic efficacy of 0.2 mg SE for the treatment of HAND was assessed to address two key questions in the HIV-1 transgenic (Tg) rat. First, does SE exhibit robust therapeutic efficacy when treatment is initiated relatively early (i.e., between 2 and 3 months of age) in the course of viral protein exposure? Second, does the therapeutic utility of SE generalize across multiple neurocognitive domains? Treatment with SE enhanced preattentive processes and stimulus-response learning to the level of controls in all (i.e., 100%) HIV-1 Tg animals. For sustained and selective attention, statistically significant effects were not observed in the overall analyses (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). However, given our a priori hypothesis, subsequent analyses were conducted, revealing enhanced sustained and selective attention, approximating controls, in a subset (i.e., 50%, n = 5 and 80%, n = 8, respectively) of HIV-1 Tg animals treated with SE. Thus, the therapeutic efficacy of SE is greater when treatment is initiated relatively early in the course of viral protein exposure and generalizes across neurocognitive domains, supporting an adjunctive therapeutic for HAND in the post-cART era.

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Different roles of frontal versus striatal atrophy in HIV‐associated neurocognitive disorders

Cited by 37 publications

References 92 publications

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV

Altered Gray Matter Volume and Functional Connectivity in Human Immunodeficiency Virus-Infected Adults

Selective Estrogen Receptor β Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders

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