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      Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals

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          Abstract

          Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm 3) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains ( p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects ( p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected ( p = 0.008), but FC differences became non-significant after treatment ( p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics. Conclusions: Twelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively preserved immune function. Longer periods of observation are necessary to assess whether this effect is maintained.

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          The online version of this article (doi:10.1007/s13365-017-0553-9) contains supplementary material, which is available to authorized users.

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          Development of functional and structural connectivity within the default mode network in young children.

          Kaustubh Supekar, Lucina Q. Uddin, Katherine Prater … (2010)
          Functional and structural maturation of networks comprised of discrete regions is an important aspect of brain development. The default-mode network (DMN) is a prominent network which includes the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), medial temporal lobes (MTL), and angular gyrus (AG). Despite increasing interest in DMN function, little is known about its maturation from childhood to adulthood. Here we examine developmental changes in DMN connectivity using a multimodal imaging approach by combining resting-state fMRI, voxel-based morphometry and diffusion tensor imaging-based tractography. We found that the DMN undergoes significant developmental changes in functional and structural connectivity, but these changes are not uniform across all DMN nodes. Convergent structural and functional connectivity analyses suggest that PCC-mPFC connectivity along the cingulum bundle is the most immature link in the DMN of children. Both PCC and mPFC also showed gray matter volume differences, as well as prominent macrostructural and microstructural differences in the dorsal cingulum bundle linking these regions. Notably, structural connectivity between PCC and left MTL was either weak or non-existent in children, even though functional connectivity did not differ from that of adults. These results imply that functional connectivity in children can reach adult-like levels despite weak structural connectivity. We propose that maturation of PCC-mPFC structural connectivity plays an important role in the development of self-related and social-cognitive functions that emerge during adolescence. More generally, our study demonstrates how quantitative multimodal analysis of anatomy and connectivity allows us to better characterize the heterogeneous development and maturation of brain networks. Copyright 2010 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 170 times – based on 0 reviews     Review now
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            The AIDS dementia complex: II. Neuropathology.

            E. Cho, B Navia, Ashleigh R. Price … (1986)
            In order to define the histopathological substrate of the dementia that frequently complicates the acquired immune deficiency syndrome (AIDS), we analyzed the neuropathological findings in 70 autopsied adult AIDS patients, 46 of whom had suffered clinically overt dementia. Less than 10% of the brains were histologically normal. Abnormalities were found predominantly in the white matter and in subcortical structures, with relative sparing of the cortex. Their frequency and severity generally correlated well with the degree and duration of clinical dementia. Most commonly noted was diffuse pallor in the white matter, which in the pathologically milder cases was accompanied by scanty perivascular infiltrates of lymphocytes and brown-pigmented macrophages, and in the most advanced cases by clusters of foamy macrophages and multinucleated cells associated with multifocal rarefaction of the white matter. However, in nearly one third of the demented cases the histopathological findings were remarkably bland in relation to the severity of clinical dysfunction. In addition, similar mild changes were noted in over one half of the nondemented patients, consistent with subclinical involvement. Vacuolar myelopathy was found in 23 patients and was generally more common and severe in patients with advanced brain pathology. Evidence of cytomegalovirus (CMV) infection was noted in nearly one quarter of the brains and was associated with a relative abundance of microglial nodules, but correlated neither with the major subcortical neuropathology nor with the clinical dementia, indicating that CMV infection likely represented a second, superimposed process. This study establishes the AIDS dementia complex as a distinct clinical and pathological entity and, together with accumulating virological evidence, suggests that it is caused by direct LAV/HTLV-III brain infection.
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              Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance.

              R. Ellis, David Clifford, … (2009)
              To determine whether antiretroviral regimens with good central nervous system (CNS) penetration control HIV in cerebrospinal fluid (CSF) and improve cognition. Multisite longitudinal observational study. Research clinics. One hundred and one individuals with advanced HIV beginning or changing a new potent antiretroviral regimen were enrolled in the study. Data for 79 participants were analyzed. Participants underwent structured history and neurological examination, venipuncture, lumbar puncture, and neuropsychological tests at entry, 24, and 52 weeks. Antiretroviral regimens were categorized as CNS penetration effectiveness (CPE) rank of at least 2 or less than 2. Generalized estimating equations were used to examine associations over the course of the study. Concentration of HIV RNA in CSF and blood and neuropsychological test scores (NPZ4 and NPZ8). Odds of suppression of CSF HIV RNA were higher when CPE rank was at least 2 than when it was less than 2. Odds of suppression of plasma HIV RNA were not associated with CPE rank. Among participants with impaired neuropsychological performance at entry, those prescribed regimens with a CPE rank of at least 2 or more antiretrovirals had lower composite NPZ4 scores over the course of the study. Antiretroviral regimens with good CNS penetration, as assessed by CPE rank, are more effective in controlling CSF (and presumably CNS) viral replication than regimens with poorer penetration. In this study, antiretrovirals with good CNS penetration were associated with poorer neurocognitive performance. A larger controlled trial is required before any conclusions regarding the influence of specific antiretrovirals on neurocognitive performance should be made.
              Article 0 comments Cited 73 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Giovanni Schifitto: (585)275-3052 , Giovanni_Schifitto@URMC.Rochester.edu
                Journal
                Journal ID (nlm-ta): J Neurovirol
                Journal ID (iso-abbrev): J. Neurovirol
                Title: Journal of Neurovirology
                Publisher: Springer International Publishing (Cham )
                ISSN (Print): 1355-0284
                ISSN (Electronic): 1538-2443
                Publication date (Electronic): 8 August 2017
                Publication date PMC-release: 8 August 2017
                Publication date (Print): 2017
                Volume: 23
                Issue: 5
                Pages: 704-712
                Affiliations
                [1 ]ISNI 0000 0004 1936 9174, GRID grid.16416.34, Department of Electrical and Computer Engineering, , University of Rochester, ; Rochester, NY USA
                [2 ]ISNI 0000 0004 1936 9166, GRID grid.412750.5, Department of Biostatistics and Computational Biology, School of Medicine and Dentistry, , University of Rochester Medical Center, ; Rochester, NY USA
                [3 ]ISNI 0000 0004 1936 9887, GRID grid.273335.3, Department of Pharmacy Practice, , University at Buffalo, ; Buffalo, NY USA
                [4 ]ISNI 0000 0001 0668 7243, GRID grid.266093.8, Department of Neurology, , University of California, Irvine School of Medicine, ; Irvine, CA USA
                [5 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Internal Medicine, , University of Texas Southwestern Medical Center, ; Dallas, TX USA
                [6 ]ISNI 0000 0004 1936 9166, GRID grid.412750.5, Department of Neurology, School of Medicine and Dentistry, , University of Rochester Medical Center, ; Rochester, NY USA
                [7 ]ISNI 0000 0004 1936 9166, GRID grid.412750.5, Department of Imaging Sciences, School of Medicine and Dentistry, , University of Rochester Medical Center, ; 601 Elmwood Ave, Box 673, Rochester, NY 14642 USA
                [8 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Psychiatry and Bio-behavioral Sciences, , University of California, ; Los Angeles, CA USA
                [9 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Division of Infectious Diseases, Department of Internal Medicine, , The University of Texas Health Science Center at Houston, ; Houston, TX USA
                Article
                Publisher ID: 553
                DOI: 10.1007/s13365-017-0553-9
                PMC ID: 5655604
                PubMed ID: 28791662
                SO-VID: 89b1ffc0-1b52-4309-9e8f-e9a6a1155386
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 27 February 2017
                Date revision received : 20 May 2017
                Date accepted : 10 July 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 MH099921
                Award ID: R01 HL123346
                Award ID: UL1TR002001
                Award ID: P30 AI078498-08
                Award Recipient :
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Journal of NeuroVirology, Inc. 2017

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: hiv infection,combination antiretroviral therapy,functional magnetic resonance imaging,diffusion tensor imaging,cognitive function
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: hiv infection, combination antiretroviral therapy, functional magnetic resonance imaging, diffusion tensor imaging, cognitive function

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