title: Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda.
abstract: In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/μL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid β42. Individuals with CD4 351-500 cells/μL (N = 40) had significantly higher CSF levels of interleukin (IL)-1β, amyloid β42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.
authors.affiliation: University of Minnesota, Minneapolis, MN.|Infectious Diseases Institute, Kampala, Uganda.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Abassi
authors.affiliation: University of Minnesota, Minneapolis, MN.|Infectious Diseases Institute, Kampala, Uganda.
authors.forename: Bozena M
authors.initials: BM
authors.lastname: Morawski
authors.affiliation: Rakai Health Sciences Program, Entebbe, Uganda.
authors.forename: Gertrude
authors.initials: G
authors.lastname: Nakigozi
authors.affiliation: Infectious Diseases Institute, Kampala, Uganda.|Makerere University, Kampala, Uganda.
authors.forename: Noeline
authors.initials: N
authors.lastname: Nakasujja
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Kong
authors.affiliation: University of Minnesota, Minneapolis, MN.|Infectious Diseases Institute, Kampala, Uganda.|Makerere University, Kampala, Uganda.
authors.forename: David B
authors.initials: DB
authors.lastname: Meya
authors.affiliation: University of North Carolina, Chapel Hill, NC.
authors.forename: Kevin
authors.initials: K
authors.lastname: Robertson
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Ronald
authors.initials: R
authors.lastname: Gray
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Ned
authors.initials: N
authors.lastname: Sacktor
authors.affiliation: University of Minnesota, Minneapolis, MN.
authors.forename: David R
authors.initials: DR
authors.lastname: Boulware
mesh_terms: D015526:AIDS Dementia Complex / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000276:immunology / Q000503:physiopathology; D000328:Adult; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000276:immunology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D019208:Brain-Derived Neurotrophic Factor / Q000134:cerebrospinal fluid / Q000276:immunology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000134:cerebrospinal fluid / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000134:cerebrospinal fluid / Q000276:immunology; D007376:Interleukin-2 / Q000134:cerebrospinal fluid / Q000276:immunology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000134:cerebrospinal fluid / Q000276:immunology; D020783:Matrix Metalloproteinase 7 / Q000134:cerebrospinal fluid / Q000276:immunology; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000276:immunology; D010982:Platelet-Derived Growth Factor / Q000134:cerebrospinal fluid / Q000276:immunology; D011446:Prospective Studies; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood / Q000276:immunology; D064568:S100 Calcium Binding Protein beta Subunit / Q000134:cerebrospinal fluid / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid / Q000276:immunology; D014454:Uganda
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018664:Interleukin-12; D007376:Interleukin-2; D020781:Matrix Metalloproteinase 1; D020783:Matrix Metalloproteinase 7; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D000067759:Receptor for Advanced Glycation End Products; D064568:S100 Calcium Binding Protein beta Subunit; D014409:Tumor Necrosis Factor-alpha; C579160:S100B protein, human; C075222:amyloid beta-protein (1-42); C075278:platelet-derived growth factor A; C579455:BDNF protein, human; C060932:MMP7 protein, human; C522360:MMP1 protein, human; C000593871:AGER protein, human
keywords: Cytokine expression; Dementia; HIV-associated neurocognitive disorders; Inflammation; Neurodegenerative biomarkers