PET brain imaging in HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy

Vera, Jaime H.; Ridha, Basil H.; Gilleece, Yvonne; Amlani, Aliza; Thorburn, P T; Dizdarevic, Sabina

doi:10.1007/s00259-016-3602-3

Cited by 27 publications

(18 citation statements)

References 59 publications

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“…Imaging with the second-generation ligand DPA-713 revealed signi cant abnormalities in the frontal cortex of HIV-infected persons with severe cognitive impairment (29). A more recent association study found positive correlation between increased DPA-713 uptake and neurocognitive performance in treated-HIV-infected persons in line with prior human imaging studies (28,(46)(47)(48).…”

Section: Discussionsupporting

confidence: 59%

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

Mahmud

Greif

et al. 2020

Preprint

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Background Osteopontin (OPN) as a secreted signaling protein, is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts, poorly understood. Methods Positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain, is a non-invasive tool used to track neuroinflammation in living mammals. Results In humanized, chronically HIV-infected mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand, DPA-713 was markedly upregulated in the hippocampus, cortex, olfactory bulb, cerebellum and significantly increased in other key brain regions analyzed compared to controls. TSPO+ microglia were detected by immunolabeling of post-mortem brain tissue, thus validating the neuroimaging findings. Unexpectedly, two types of neurons also selectively stained positively for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase positive neurons of the substantia nigra. Two-way ANOVA of immunoreactivity revealed that a well-validated marker of microglial activation in brain tissue, ionized calcium-binding adaptor molecule-1 (Iba-1) was significantly increased, in an interaction that depended on HIV replication. Interestingly, similar analyses of TSPO immunoreactivity showed a significant interaction with OPN expression. Conclusions Collectively, these findings using a model of chronic HIV-infection revealed for the first time two key findings: 1) two different pathways of neuroinflammation are activated, and 2) osteopontin acts as a molecular brake regulating in the brain, the inflammatory response to HIV infection.

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Section: Discussionsupporting

confidence: 59%

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

Mahmud

Greif

et al. 2020

Preprint

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“…[5, 94-96] The amyloid PET/CT with florbetaben confirmed amyloid deposition in the frontal, temporal and parietal lobes bilaterally including the posterior cingulate and precuneus, a pattern consistent with AD. [5] Recently, a case study showed frontal, parietal and temporal hypometabolism on FDG-PET in a 70-year old HIV-infected individual with CD4 cell count of 124 presenting with memory deficits for the 4 months, apraxia and incontinence.…”

Section: Neuroimagingmentioning

confidence: 99%

Differentiating HIV-Associated Neurocognitive Disorders From Alzheimer’s Disease: an Emerging Issue in Geriatric NeuroHIV

Milanini

Valcour

2017

Curr HIV/AIDS Rep

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Purpose of Review To examine characteristics that may distinguish HIV-associated Neurocognitive Disorder (HAND) from early Alzheimer's disease (AD) Recent Findings CSF AD biomarkers are perturbed in HIV, yet these alterations may be limited to settings of advanced dementia or unsuppressed plasma HIV RNA. Neuropsychological testing will require extensive batteries to maximize utility. Structural imaging is limited for early AD detection in the setting of HIV, but proper studies are absent. While positron emission tomography (PET) amyloid imaging has altered the landscape of differential diagnosis for age-associated neurodegenerative disorders, costs are prohibitive. Summary Risk for delayed AD diagnosis in the aging HIV-infected population is now among the most pressing issues in geriatric neuro HIV. While clinical, imaging, and biomarker characterization of AD is extensively defined, fewer data define characteristics of HAND in the setting of suppressed plasma HIV RNA. Data needed to inform the phenotype of AD in the setting of HIV are equally few.

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“…PET has been used for the differential diagnosis of primary, opportunistic and neoplastic CNS lesions in human immunodeficiency virus (HIV) carriers. In HIV-infected individuals with cognitive impairment the 18F-FDG PET has shown subcortical hypermetabolism in the basal ganglia, striatum and thalamus, with discretely increased metabolism in studies following the introduction of combined antiretroviral therapy [ 17 ]. We hypothesized that in the early stages of HTLV-1 spinal cord impairment, 18F-FDG PET/CT would show a metabolic increase due to inflammation.…”

Section: Introductionmentioning

confidence: 99%

Spinal cord hypometabolism associated with infection by human T-cell lymphotropic virus type 1(HTLV-1)

et al. 2018

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BackgroundHTLV-1 infection is endemic in Brazil. About 1 to 2% of the Brazilian population is estimated to be infected, but most infected HTLV-1 individuals do not know about their own infection, which favors the continuity of sexual and vertical virus transmission. In addition, HTLV-1 associated central nervous system diseases and their pathophysiologic mechanisms are not fully understood. This study aimed to evaluate the correlation of spinal cord metabolism, viral and inflammatory profiles with features of neurological presentation in HTLV-1 infected individuals.MethodologyThis is a cross-sectional study of a cohort including 48 HTLV-1 infected individuals clinically classified as asymptomatic-AG (N = 21), symptomatic-SG (N = 11) and HAM/TSP-HG (N = 16) and a nested case-control study with HTLV-1 infected individuals-HIG (N = 48) and HTLV-1 non infected controls-CG (N = 30) that had their spinal cord analysed by Positron Emission Tomography with 18F-Fluordeoxyglucose (18F-FDG PET/CT). HTLV-1 infected individuals had 18F-FDG PET/CT results analyzed with clinical and demographic data, proviral load, cytokines and chemokines in the blood and cerebrospinal fluid (CSF).Principal Findings18F-FDG PET/CT showed hypometabolism in the thoracic spinal cord in HTLV-1 infected individuals. The method had an accuracy of 94.4% to identify HAM/TSP. A greater involvement of the thoracic spinal cord was observed, although hypometabolism was also observed in the cervical spinal cord segment in HTLV-1 infected individuals. Individuals with HAM/TSP showed a pro-inflammatory profile in comparison to asymptomatic and symptomatic groups, with a higher level of Interferon-inducible T-cell alpha chemoattractant (ITAC/CXCL11), IL-6, IL-12p70 in the plasma; and ITAC, IL-4, IL-5, IL-8 (CXCL8) and TNF-alpha in the CSF. Using regression, thoracic spinal cord SUV (standardized uptake value) and CSF ITAC level were identified as the HAM/TSP predictors in the multivariate model.Conclusions18F-FDG PET/CT imaging showed spinal cord hypometabolism in most HTLV-1 infected individuals, even in the asymptomatic HTLV-1 group. Thoracic spinal cord hypometabolism and CSF-ITAC levels were identified predictors of HAM/TSP.SignificanceOur findings suggested that in most HTLV-1 infected individuals there was compromise of central nervous system (CNS) structures despite of the lack of clinical symptoms. To explain the found hypometabolism, the role of microcirculatory and metabolic factors in the pathogenesis of neurological diseases associated with HTLV-1 infection must be further investigated. It is paramount to evaluate the central nervous function and to compare the performance among HTLV-1 infected individuals considered asymptomatic to the uninfected controls.

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PET brain imaging in HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy

Cited by 27 publications

References 59 publications

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

Osteopontin/Secreted Phosphoprotein-1 Behaves as a Molecular Brake Regulating the Brain Translocator Protein-Dependent Neuroinflammatory Response to Chronic Viral Infection

Differentiating HIV-Associated Neurocognitive Disorders From Alzheimer’s Disease: an Emerging Issue in Geriatric NeuroHIV

Spinal cord hypometabolism associated with infection by human T-cell lymphotropic virus type 1(HTLV-1)

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