Preliminary In Vivo Evidence of Reduced Synaptic Density in Human Immunodeficiency Virus (HIV) Despite Antiretroviral Therapy

Weiss, J. Woodrow; Calvi, Rachela; Naganawa, Mika; Toyonaga, Takuya; Farhadian, Shelli; Chintanaphol, Michelle; Chiarella, Jennifer; Zheng, Ming-Qiang; Ropchan, Jim; Huang, Yiyun; Pietrzak, Robert H.; Carson, Richard E.; Spudich, Serena

doi:10.1093/cid/ciab484

Cited by 27 publications

(19 citation statements)

References 57 publications

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“…Synapse density. Synapse density in the cortex was measured in 76 healthy adults (45 males, 48.9 ± 18.4 years of age) by administering ½ 11 CUCB-J, a PET tracer that binds to the synaptic vesicle glycoprotein 2A (SV2A) [150][151][152][153][154][155][156][157][158][159][160][161] . Data were collected on an HRRT PET camera for 90 min post injection.…”

Section: Molecular Predictorsmentioning

confidence: 99%

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

et al. 2022

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Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

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Section: Molecular Predictorsmentioning

confidence: 99%

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

et al. 2022

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“…Recently, SV2A imaging was also applied to patients with HIV infection, as synaptic loss is a common hallmark of this condition. SV2A density was found to be reduced in the fronto-striatal-thalamic regions and other cortical areas of patients compared to control subjects ( Weiss et al, 2021 ).…”

Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

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“…This shows that astrovirus infection of neurons impacts neurophysiology by disrupting synaptic integrity, triggering a loss of afferent innervation related to infected neurons, and impairing both excitatory and inhibitory neurotransmission. To date, relatively few studies have investigated the downregulation of expression of neural genes [17,27] or synaptic degeneration and loss [28][29][30][31][32] in postmortem brains of humans who died from CNS infections caused by viruses (e.g., HIV and WNV). However, there are many examples of downregulation of neural functions at the gene and protein level, as well as synaptic pathology, in animal studies of CNS infections caused by various viruses [21,[33][34][35].…”

Section: Discussionmentioning

confidence: 99%

Imbalanced immune response and dysregulation of neural functions underline fatal opportunistic encephalitis caused by astrovirus

Maximova

Weller

Krogmann

et al. 2022

Preprint

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The incidence of infections of the central nervous system (CNS) in humans is increasing due to emergence and re-emergence of pathogens and an increase in the number of immunocompromised patients. Many viruses are opportunists and can invade the CNS if the immune response of the host is impaired. Here we investigate neuropathogenesis of a rare CNS infection in immunocompromised patients caused by astrovirus and show that it shares many features with another opportunistic infection of the CNS caused by human immunodeficiency virus. We show that astrovirus infects CNS neurons with a major impact on the brainstem. In the setting of impaired peripheral adaptive immunity, host responses in the astrovirus infected brain are skewed to the innate immune response with exuberant activation of microglia and macrophages. Astrovirus infection of neurons and responses by phagocytic cells lead to disrupted synaptic integrity, loss of afferent innervation related to infected neurons, and global impairment of both excitatory and inhibitory neurotransmission. The response employed in the CNS against opportunistic viruses, such as astrovirus and HIV, may be a common compensatory defense mechanism which inadvertently leads to loss of neural functions due to the host’s exuberant innate immune response to pathogens when adaptive immunity is impaired.

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Preliminary In Vivo Evidence of Reduced Synaptic Density in Human Immunodeficiency Virus (HIV) Despite Antiretroviral Therapy

Cited by 27 publications

References 57 publications

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Synaptic Vesicle Glycoprotein 2A: Features and Functions

Imbalanced immune response and dysregulation of neural functions underline fatal opportunistic encephalitis caused by astrovirus

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