title: Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection.
abstract: The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management.
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Peterson
authors.affiliation: Department of Infectious Diseases, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Gisslen
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Division of Biological Chemistry, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, United States of America.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Shacklett
authors.affiliation: Department of Infectious Diseases, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Hagberg
authors.affiliation: Department of Biostatistics, Indiana University, R.M. Fairbanks School of Public Health, Indianapolis, IN, United States of America.
authors.forename: Constantin T
authors.initials: CT
authors.lastname: Yiannoutsos
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT, United States of America.
authors.forename: Serena S
authors.initials: SS
authors.lastname: Spudich
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Price
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003430:Cross-Sectional Studies; D005260:Female; D006678:HIV / Q000302:isolation & purification; D015658:HIV Infections / Q000134:cerebrospinal fluid* / Q000150:complications / Q000175:diagnosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid* / Q000150:complications; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D016900:Neurofilament Proteins; D010446:Peptide Fragments; C044882:neurofilament protein L; D016875:tau Proteins