Advertisement

Diagnostic and prognostic biomarkers for HAND

  • Kristen A. McLaurin
  • Rosemarie M. Booze
  • Charles F. Mactutus
Article

Abstract

In 2007, the nosology for HIV-1-associated neurocognitive disorders (HAND) was updated to a primarily neurocognitive disorder. However, currently available diagnostic tools lack the sensitivity and specificity needed for an accurate diagnosis for HAND. Scientists and clinicians, therefore, have been on a quest for an innovative biomarker to diagnose (i.e., diagnostic biomarker) and/or predict (i.e., prognostic biomarker) the progression of HAND in the post-combination antiretroviral therapy (cART) era. The present review examined the utility and challenges of four proposed biomarkers, including neurofilament light (NFL) chain concentration, amyloid (i.e., sAPPα, sAPPβ, amyloid β) and tau proteins (i.e., total tau, phosphorylated tau), resting-state functional magnetic resonance imaging (fMRI), and prepulse inhibition (PPI). Although significant genotypic differences have been observed in NFL chain concentration, sAPPα, sAPPβ, amyloid β, total tau, phosphorylated tau, and resting-state fMRI, inconsistencies and/or assessment limitations (e.g., invasive procedures, lack of disease specificity, cost) challenge their utility as a diagnostic and/or prognostic biomarker for milder forms of neurocognitive impairment (NCI) in the post-cART era. However, critical evaluation of the literature supports the utility of PPI as a powerful diagnostic biomarker with high accuracy (i.e., 86.7–97.1%), sensitivity (i.e., 89.3–100%), and specificity (i.e., 79.5–94.1%). Additionally, the inclusion of multiple CSF and/or plasma markers, rather than a single protein, may provide a more sensitive diagnostic biomarker for HAND; however, a pressing need for additional research remains. Most notably, PPI may serve as a prognostic biomarker for milder forms of NCI, evidenced by its ability to predict later NCI in higher-order cognitive domains with regression coefficients (i.e., r) greater than 0.8. Thus, PPI heralds an opportunity for the development of a brief, noninvasive diagnostic and promising prognostic biomarker for milder forms of NCI in the post-cART era.

Keywords

Diagnostic biomarker Prognostic biomarker HIV-1-associated neurocognitive disorders Prepulse inhibition 

Notes

Funding information

This work was supported in part by grants from NIH (National Institute on Drug Abuse, DA013137; National Institute of Child Health and Human Development, HD043680; National Institute of Mental Health, MH106392; National Institute of Neurological Disorders and Stroke, NS100624) and the interdisciplinary research training program supported by the University of South Carolina Behavioral-Biomedical Interface Program.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Abdulle S, Mellgren A, Brew BJ, Cinque P, Hagberg L, Price RW, Rosengren L, Gisslén M (2007) CSF neurofilament protein (NFL)—a marker of active HIV-related neurodegeneration. J Neurol 254:1026–1032.  https://doi.org/10.1007/s00415-006-0481-8 CrossRefPubMedGoogle Scholar
  2. Abidin AZ, Dsouza AM, Nagarajan MB, Wang L, Qiu X, Schifitto G, Wismuller A (2018) Alteration of brain network topology in HIV-associated neurocognitive disorder: a novel functional connectivity perspective. Neuroimage Clin 17:768–777.  https://doi.org/10.1016/j.nicl.2017.11.025 CrossRefPubMedGoogle Scholar
  3. Achim CL, Adame A, Dumaop W, Everall IP, Masliah E, Neurobehavioral Research Center (2009) Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J NeuroImmune Pharmacol 4:190–199.  https://doi.org/10.1007/s11481-009-9152-8 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ances BM, Vaida F, Yeh MJ, Liang CL, Buxton RB, Letendre S, McCutchan JA, Ellis RJ, the HIV Neurobehavioral Research (2010) HIV and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis 201:336–340.  https://doi.org/10.1086/649899 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Anderson AM, Easley KA, Kasher N, Franklin D, Heaton RK, Zetterberg H, Blennow K, Gisslén M, Letendre SL (2018) Neurofilament light chain in blood is negatively associated with neuropsychological performance in HIV-infected adults and declines with initiation of antiretroviral therapy. J Neurovirol  https://doi.org/10.1007/s13365-018-0664-y
  6. Ann HW, Jun S, Shin N, Han S, Ahn JY, Ahn MY, Jeon YD, Jung IY, Kim MH, Jeong WY, Ku NA, Kim JM, Smith DM, Choi JY (2016) Characteristics of resting-state functional connectivity in HIV-associated neurocognitive disorders. PLoS One 11:e0153493.  https://doi.org/10.1371/journal.pone.0153493 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2006) Accelerated tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retoviral therapy. Acta Neuropathol 111:529–538.  https://doi.org/10.1007/s00401-006-0037-0 CrossRefPubMedGoogle Scholar
  8. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslén M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799.  https://doi.org/10.1212/01.WNL.0000287431.88658.8b CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bachis A, Forcelli P, Masliah E, Campbell L, Mocchetti I (2016) Expression of gp120 in mice evokes anxiety behavior: co-occurrence with increased dendritic spines and brain-derived neurotrophic factor in the amygdala. Brain Behav Immun 54:170–177.  https://doi.org/10.1016/j.bbi.2016.01.020 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee J-M, Holtzman DM (2011) Neuronal activity regulates the regional vulnerability to amyloid-b deposition. Nat Neurosci 14:750–756.  https://doi.org/10.1038/nn.2801 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Billnitzer AJ, Barskaya I, Yin C, Perez RG (2013) APP independent and dependent effects on neurite outgrowth are modulated by the receptor associated protein (RAP). J Neurochem 124:123–132.  https://doi.org/10.1111/jnc.12051 CrossRefPubMedGoogle Scholar
  12. Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371–1378CrossRefGoogle Scholar
  13. Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95.  https://doi.org/10.1067/mcp.2001.113989 CrossRefGoogle Scholar
  14. Blumenthal TD, Cuthbert BN, Filion DL, Hackley S, Lipp OV, van Boxtel A (2005) Committee report: guidelines for human startle eyeblink electromyographic studies. Psychophysiology 42:1–15.  https://doi.org/10.1111/j.1469-8986.2005.00271.x CrossRefPubMedGoogle Scholar
  15. Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978) Prestimulus effects on human startle reflex in normal and schizophrenics. Psychophysiology 15:339–343.  https://doi.org/10.1111/j.1469-8986.1978.tb01390.x CrossRefPubMedGoogle Scholar
  16. Brys M, Pirraglia E, Rich K, Rolstad S, Mosconi L, Switalski R, Glodzik-Sobanska L, De Santi S, Zinkowski R, Mehta P, Pratico D, Saint Louis LA, Wallin A, Blennow K, de Leon MJ (2009) Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment. Neurobiol Aging 30:682–690.  https://doi.org/10.1016/j.neurobiolaging.2007.08.010 CrossRefPubMedGoogle Scholar
  17. Bubser M, Koch M (1994) Prepulse inhibition of the acoustic startle response of rats is reduced by 6-hydroxydopamine lesions of the medial prefrontal cortex. Psychopharmacology 113:487–492CrossRefGoogle Scholar
  18. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O (2012) Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 69:98–106.  https://doi.org/10.1001/archgenpsychiatry.2011.155 CrossRefPubMedGoogle Scholar
  19. Byrne LM, Rodrigues FB, Blennow K, Durr A, Leavitt BR, Roos RAC, Scahill RI, Tabrizi SJ, Zetterberg H, Langbehn D, Wild EJ (2017) Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: a retrospective cohort analysis. Lancet Neurol 16:601–609.  https://doi.org/10.1016/S1474-4422(17)30124-2 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Campeau S, Davis M (1995) Prepulse inhibition of the acoustic startle reflex usingvisual and auditory prepulses: disruption by apomorphine. Psychopharmacology 17:267–274CrossRefGoogle Scholar
  21. Cai L, Huang J (2018) Neurofilament light chain as a biological marker for multiple sclerosis: a meta-analysis study. Neuropsychiatr Dis Treat 14:2241–2254.  https://doi.org/10.2147/NDT.S173280 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Carey CL, Woods SP, Rippeth JD, Heaton RK, Grant I, the HIV Neurobehavioral Research Center (HNRC) Group (2006) Prospective memory in HIV-1 infection. J Clin Exp Neuropsychol 28:536–548.  https://doi.org/10.1080/13803390590949494 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Casey BJ, Matthew D, Rosen B (2002) Functional magnetic resonance imaging: basic principles of and application to developmental science. Dev Sci 5:301–309.  https://doi.org/10.1111/1467-7687.00370 CrossRefGoogle Scholar
  24. Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL, Hallett M (1996) Sensorimotor gating in boys with Tourette’s syndrome and ADHD: preliminary results. Biol Psychiatry 39:33–41.  https://doi.org/10.1016/0006-3223(95)00101-8 CrossRefPubMedGoogle Scholar
  25. Centers for Disease Control and Prevention (2018) HIV among people aged 50 and older. https://www.cdc.gov/hiv/group/age/olderamericans/index.html
  26. Chaganti JR, Heinecke A, Gates TM, Moffat KJ, Brew BJ (2017) Functional connectivity in virally suppressed patients with HIV-associated neurocognitive disorder: a resting-state analysis. AJNR Am J Neuroradiol 38:1623–1629.  https://doi.org/10.3174/ajnr.A5246 CrossRefPubMedGoogle Scholar
  27. Chan P, Brew BJ (2014) HIV associated neurocognitive disorders in the modern antiviral treatment era: prevalence, characteristics, biomarkers, and effects of treatment. Curr HIV/AIDS Rep 11:317–324.  https://doi.org/10.1007/s11904-014-0221-0 CrossRefPubMedGoogle Scholar
  28. Chang L, Wang GJ, Volkow ND, Ernst T, Telang F, Logan J, Fowler JS (2008) Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with or without cocaine abuse. Neuroimage 42:869–878.  https://doi.org/10.1016/j.neuroimage.2008.05.011 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE (2017) Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 38:1205–1235.  https://doi.org/10.1038/aps.2017.28 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Chiu MJ, Chen YF, Chen TF, Yang SY, Yang FPG, Tseng TW, Chieh JJ, Chen JCR, Tzen KY, Hua MS, Horng HE (2013) Plasma tau as a window to the brain—negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer’s disease. Hum Brain Mapp 7:3132–3142.  https://doi.org/10.1002/hbm.22390 CrossRefGoogle Scholar
  31. Cirrito JR, Kang J-E, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58:42–51.  https://doi.org/10.1016/j.neuron.2008.02.003 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Clifford DB, Fagan AM, Holtzman DM, Morris JC, Teshome M, Shah AR, Kauwe JSK (2009) CSF biomarkers of Alzheimer’s disease in HIV-associated neurologic disease. Neurology 73:1982–1987.  https://doi.org/10.1212/WNL.0b013e3181c5b445 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Cole JH, Caan MWA, Underwood J, De Francesco D, van Zoest RA, Wit FWNM, Mutsaerts HJMM, Leech R, Geurtsen GJ, Portegies P, Majoie CBLM, Schim van der Loeff MR, Sabin CA, Reiss P, Winston A, Sharp DJ, Comorbidity in Relations to AIDS (COBRA) Collaboration (2018) No evidence for accelerated aging-related brain pathology in treated human immunodeficiency virus: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project. Clin Infect Dis 66:1899–1909.  https://doi.org/10.1093/cid/cix1124 CrossRefPubMedGoogle Scholar
  34. Dage JL, Wennberg AMV, Airey DC, Hagen CE, Knopman DS, Machulda MM, Roberts RO, Jack CR Jr, Petersen RC, Mielke MM (2016) Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort. Alzheimers Dement 12:1226–1234.  https://doi.org/10.1016/j.jalz.2016.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
  35. De Almeida SM, Ribeiro CE, Rotta I, Piovesan M, Tang B, Vaida F, Raboni SM, Letendre S, Potter M, Batistela Fernandes MS, Ellis RJ, HIV Neurobehavioral Research Center (HNRC) Group (2018) Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patient infected with HIV-1 subtypes B and C. J Neuro-Oncol 24:28–40.  https://doi.org/10.1007/s13365-017-0591-3 CrossRefGoogle Scholar
  36. Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, Ellis R, Cherner M, Grant I, Masliah E (2013) Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 80:1415–1423.  https://doi.org/10.1212/WNL.0b013e31828c2e9e CrossRefPubMedPubMedCentralGoogle Scholar
  37. De Strooper B, Annaert W (2000) Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 113:1857–1870PubMedGoogle Scholar
  38. Di Rocco A, Bottiglieri T, Dorfman D, Werner P, Morrison C, Simpson D (2000) Decreased homovanilic acid in cerebrospinal fluid correlates with impaired neuropsychologic function in HIV-1-infected patients. Clin Neuropharmacol 23:19–194CrossRefGoogle Scholar
  39. Donker Kaat L, Meeter LH, Chiu WZ, Melhem S, Boon AJW, Blennow K, Zetterberg H, van Swieten JC (2018) Serum neurofilament light chain in progressive supranuclear palsy. Parkinsonism Relat Disord  https://doi.org/10.1016/j.parkreldis.2018.06.018
  40. Dsouza AM, Abidin AZ, Wismϋller A (2017) Investigating changes in resting-state connectivity from functional MRI data in patients with HIV associated neurocognitive disorder using MCA and machine learning. Proc SPIE Int Soc Opt Eng 10137:101371C.  https://doi.org/10.1117/12.2254189 CrossRefPubMedPubMedCentralGoogle Scholar
  41. du Plessis L, Paul RH, Hoare J, Stein DJ, Taylor PA, Meintjes EM, Joska JA (2017) Resting-state functional magnetic resonance imaging in clade C HIV: within-group association with neurocognitive function. J Neuro-Oncol 23:875–885.  https://doi.org/10.1007/s13365-017-0581-5
  42. Egbert AR, Biswal B, Karunakaran K, Gohel S, Pluta A, Wolak T, Szymanska B, Firlag-Burkacka E, Sobanska M, Gawron N, Bienkowski P, Sienkiewicz-Jarosz H, Scinska-Bienkowska A, Bornstein R, Rao S, Lojek E (2018) Age and HIV effects on resting state of the brain in relationship to neurocognitive functioning. Behav Brain Res 344:20–27.  https://doi.org/10.1016/j.bbr.2018.02.007 CrossRefPubMedGoogle Scholar
  43. Egbert AR, Biswal B, Karunakaran KD, Pluta A, Wolak T, Rao S, Bornstein R, Szymanska B, Horban A, Firlag-Burkacka E, Sobanska M, Gawron N, Bienkowski P, Sienkiewicz-Jarosz H, Scinska-Bienkowska A, Lojek E (2019) HIV infection across aging: synergistic effects on intrinsic functional connectivity of the brain. Prog Neuro-Psychopharmacol Biol Psychiatry 88:19–30.  https://doi.org/10.1016/j.pnpbp.2018.06.006 CrossRefGoogle Scholar
  44. Elbirt D, Mahlab-Guri K, Bezalel-Rosenberg S, Gills H, Attali M, Asher I (2015) HIV-associated neurocognitive disorders (HAND). Isr Med Assoc J 17:54–59PubMedGoogle Scholar
  45. Ellenbroek BA, Budde S, Cools AR (1996) Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex. Neuroscience 75:535–542CrossRefGoogle Scholar
  46. Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44.  https://doi.org/10.1038/nrn2040 CrossRefPubMedGoogle Scholar
  47. FDA-NIH Biomarker Working Group (2016) BEST (Biomarkers, EndpointS, and other Tools) resource [Internet]. Silver Spring (MD): Food and Drug Administration (US). Available from: https://www.ncbi.nlm.nih.gov/books/NBK326791/ Co-published by the National Institutes of Health (US), Bethesda (MD)
  48. Fendt M, Koch M, Schnitzler HU (1994) Sensorimotor gating deficit after lesions of the superior colliculus. NeuroReport 5:1725–1738CrossRefGoogle Scholar
  49. Fendt M, Li L, Yeomans JS (2001) Brain stem circuits mediating prepulse inhibition of the startle reflex. Psychopharmacology 156:216–224CrossRefGoogle Scholar
  50. Fitting S, Booze RM, Mactutus CF (2006a) Neonatal intrahippocampal glycoprotein 120 injection: the role of dopaminergic alterations in prepulse inhibition in adult rats. J Pharmacol Exp Ther 318:1352–1358.  https://doi.org/10.1124/jpet.106.105742 CrossRefPubMedGoogle Scholar
  51. Fitting S, Booze RM, Mactutus CF (2006b) Neonatal hippocampal Tat injections: developmental effects on prepulse inhibition (PPI) of the auditory startle response. Int J Dev Neurosci 24:275–283.  https://doi.org/10.1016/j.ijdevneu.2006.02.001 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Fitting S, Booze RM, Hasselrot U, Mactutus CF (2006c) Intrahippocampus injections of Tat: effects on prepulse inhibition of the auditory startle response in adult male rats. Pharmacol Biochem Behav 84:189–196.  https://doi.org/10.1016/j.pbb.2006.04.014 CrossRefPubMedGoogle Scholar
  53. Fitting S, Booze RM, Mactutus CF (2007) Neonatal intrahippocampal gp120 injection: an examination early in development. Neurotoxicology 28:101–107.  https://doi.org/10.1016/j.neuro.2006.07.014 CrossRefPubMedGoogle Scholar
  54. Flaten MA (1993) A comparison of electromyographic and photoelectric techniques in the study of classical eyeblink conditioning and startle reflex modification. J Psychophysiol 7:230–237Google Scholar
  55. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefGoogle Scholar
  56. Fournier P, Hébert S (2013) Gap detection deficits in humans with tinnitus as assessed with the acoustic startle paradigm: does tinnitus fill in the gap? Hear Res 295:16–23.  https://doi.org/10.1016/j.heares.2012.05.011 CrossRefPubMedGoogle Scholar
  57. Fox MD, Raichle ME (2007) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8:700–711.  https://doi.org/10.1038/nrn2201 CrossRefPubMedGoogle Scholar
  58. Gelman BB, Schuenke K (2004) Brain aging in acquired immunodeficiency syndrome: increased ubiquitin-protein conjugate is correlated with decreased synaptic protein but not amyloid plaque accumulation. J Neuro-Oncol 10:98–108.  https://doi.org/10.1080/13550280490279816 CrossRefGoogle Scholar
  59. Gelman BB, Nguyen TP (2010) Synaptic proteins linked to HIV-1 infection and immunoproteasome induction: proteomic analysis of human synaptosomes. J NeuroImmune Pharmacol 5:92–102.  https://doi.org/10.1007/s11481-009-9168-0 CrossRefPubMedGoogle Scholar
  60. Gelman BB, Lisinicchia JG, Chen T, Johnson KM, Jennings K, Freeman DH Jr, Soukup VM (2012) Prefrontal dopaminergic and enkephalinergic synaptic accomodation in HIV-associated neurocognitive disorders and encephalitis. J NeuroImmune Pharmacol 7:686–700.  https://doi.org/10.1007/s11481-012-9345-4 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Gisslén M, Hagberg L, Brew BJ, Cinque P, Price RW, Rosengren L (2007) Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis 195:1774–1778.  https://doi.org/10.1086/518043 CrossRefPubMedGoogle Scholar
  62. Gisslén M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, Spudich S, Hagberg L, Rosengren L, Price RW, Zetterberg H (2009) Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol 9:63.  https://doi.org/10.1186/1471-2377-9-63 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Gisslén M, Price RW, Andreasson U, Norgren N, Nilsson S, Hagberg L, Fuchs D, Spudich S, Blennow K, Zetterberg H (2016) Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study. EBioMedicine 3:135–140.  https://doi.org/10.1016/j.ebiom.2015.11.036 CrossRefPubMedGoogle Scholar
  64. Glover GH (2011) Overview of functional magnetic resonance imaging. Neurosurg Clin N Am 22:133–139.  https://doi.org/10.1016/j.nec.2010.11.001 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989a) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526CrossRefGoogle Scholar
  66. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989b) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8:393–399CrossRefGoogle Scholar
  67. Goodman Y, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp Neurol 128:1–12.  https://doi.org/10.1006/exnr.1994.1107 CrossRefPubMedGoogle Scholar
  68. Guha A, Wang L, Tanenbaum A, Esmaeili-Firidouni P, Wedelken LA, Busovaca E, Clifford K, Desai A, Ances BM, Valcour V (2016) Intrinsic network connectivity abnormalities in HIV-infected individuals over age 60. J Neuro-Oncol 22:80–87.  https://doi.org/10.1007/s13365-015-0370-y CrossRefGoogle Scholar
  69. Gupta S, Knight AG, Gupta S, Knapp PE, Hauser KF, Keller JN, Bruce-Keller AJ (2010) HIV-Tat elicits microglial glutamate release: role of NAPDH oxidase and the cysteine-glutamate antiporter. Neurosci Lett 485:233–236.  https://doi.org/10.1016/j.neulet.2010.09.019 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Haddow LJ, Floyd S, Copas A, Gilson RJ (2013) A systematic review of the screening accuracy of the HIV Dementia Scale and International HIV Dementia Scale. PLoS One 8:e61826.  https://doi.org/10.1371/journal.pone.0061826 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Haghighi S, Andersen O, Odén A, Rosengren L (2004) Cerebrospinal fluid markers in MS patients and their healthy siblings. Acta Neurol Scand 109:97–99CrossRefGoogle Scholar
  72. Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001) HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78:457–467CrossRefGoogle Scholar
  73. Hejl AM, Glenthoj B, Mackeprang T, Hemmingsen R, Waldemar G (2004) Prepulse inhibition in patients with Alzheimer’s disease. Neurobiol Aging 25:1045–1050.  https://doi.org/10.1016/j.neurobiolaging.2003.11.005 CrossRefPubMedGoogle Scholar
  74. Henry BL, Geyer MA, Buell MR, Perry W, Young JW, Minassian A, Translational Methamphetamine AIDS Research Center (TMARC) Group (2014) Prepulse inhibition in HIV-1 gp120 transgenic mice after withdrawal from chronic methamphetamine. Behav Pharmacol 25:12–22.  https://doi.org/10.1097/FBP.0000000000000012 CrossRefPubMedPubMedCentralGoogle Scholar
  75. Herting MM, Uban KA, Williams PL, Gautam P, Huo Y, Malee K, Yogev R, Csernansky J, Wang L, Nichols S, Van Dyke R, Sowell ER (2015) Default mode connectivity in youth with perinatally acquired HIV. Medicine (Baltimore) 94:e1417.  https://doi.org/10.1097/MD.0000000000001417 CrossRefGoogle Scholar
  76. Hinkin CH, van Gorp WG, Satz P, Marcotte T, Durvasula RS, Wood S, Campbell L, Baluda MR (1996) Actual versus self-reported cognitive dysfunction in HIV-1 infection: memory-metamemory dissociations. J Clin Exp Neuropsychol 18:431–443.  https://doi.org/10.1080/01688639608408999 CrossRefPubMedGoogle Scholar
  77. Hoffman HS, Searle JL (1965) Acoustic variables in modification of startle reaction in rat. J Comp Physiol Psychol 60:53–58CrossRefGoogle Scholar
  78. Hoffman HS, Ison JR (1980) Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev 87:175–189CrossRefGoogle Scholar
  79. Hunsberger HC, Rudy CC, Batten SR, Gerhard GA, Reed MN (2015) P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway. J Neurochem 132:169–182.  https://doi.org/10.1111/jnc.12967 CrossRefPubMedGoogle Scholar
  80. Ikin AF, Sabo SL, Lanier LM, Buxbaum JD (2007) A macromolecular complex involving the amyloid precursor protein (APP) and the cytosolic adapter FE65 is a negative regulator of axon branching. Mol Cell Neurosci 35:57–63.  https://doi.org/10.1016/j.mcn.2007.02.003 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Ison JR, Hammond GR (1971) Modification of startle reflex in rat by changes in auditory and visual environments. J Comp Physiol Psychol 75:435–452CrossRefGoogle Scholar
  82. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wolfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Gotz J (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142:387–397.  https://doi.org/10.1016/j.cell.2010.06.036 CrossRefPubMedGoogle Scholar
  83. Janssen MAM, Hinne M, Janssen RJ, van Gerven MA, Steens SC, Gόraj B, Koopmans PP, Kessels RPC (2017) Resting-state subcortical functional connectivity in HIV-infected patients on long-term cART. Brain Imaging Behav 11:1555–1560.  https://doi.org/10.1007/s11682-016-9632-4 CrossRefPubMedGoogle Scholar
  84. Javadi-Paydar M, Roscoe RF Jr, Denton AR, Mactutus CF, Booze RM (2017) HIV-1 and cocaine disrupt dopamine reuptake and medium spiny neurons in female rat striatum. PLoS One 12:e0188404.  https://doi.org/10.1371/journal.pone.0188404 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Jessen Krut J, Mellberg T, Price RW, Hagberg L, Fuchs D, Rosengren L, Nilsson S, Zetterberg H, Gisslén M (2014) Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS One 9:e88591.  https://doi.org/10.1371/journal.pone.0088591 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Joska JA, Witten J, Thomas KG, Robertson C, Casson-Crook M, Roosa H, Creighton J, Lyons J, McArthur J, Sacktor NC (2016) A comparison of five brief screening tools for HIV-associated neurocognitive disorders in the USA and South Africa. AIDS Behav 20:1621–1631.  https://doi.org/10.1007/s10461-016-1316-y CrossRefPubMedPubMedCentralGoogle Scholar
  87. Justice AC (2010) HIV and aging: time for a new paradigm. Curr HIV/AIDS Rep 7:69–76.  https://doi.org/10.1007/s11904-010-0041-9 CrossRefPubMedGoogle Scholar
  88. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937CrossRefGoogle Scholar
  89. Koch M, Kungel M, Herbert H (1993) Cholinergic neurons in the pedunculopontine tegmental nucleus are involved in the mediation of prepulse inhibition of the acoustic startle response in the rat. Exp Brain Res 97:71–82CrossRefGoogle Scholar
  90. Koch M, Schnitzler HU (1997) The acoustic startle response in rats—circuits mediating evocation, inhibition and potentiation. Behav Brain Res 89:35–49CrossRefGoogle Scholar
  91. Kopeikina KJ, Polydoro M, Tai HC, Yaeger E, Carlson GA, Pitstick R, Hyman BT, Spires-Jones TL (2013) Synaptic alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol 521:1334–1353.  https://doi.org/10.1002/cne.23234 CrossRefPubMedPubMedCentralGoogle Scholar
  92. Krut JJ, Zetterberg H, Belnnow K, Cinque P, Hagberg L, Price RW, Studahl M, Gisslén M (2013) Cerebrospinal fluid Alzheimer’s biomarker profiles in CNS infections. J Neurol 260:620–626.  https://doi.org/10.1007/s00415-012-6688-y CrossRefPubMedGoogle Scholar
  93. Krogh KA, Lyddon E, Thayer SA (2015) HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism. J Neurochem 132:345–366.  https://doi.org/10.1111/jnc.12936 CrossRefGoogle Scholar
  94. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ (2008) Abeta plaques lead to abberant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59:214–225.  https://doi.org/10.1016/j.neuron.2008.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
  95. Kumar AM, Fernandez JB, Singer EJ, Commins D, Waldrop-Valverde D, Ownby RL, Kumar M (2009) Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in difference regions of postmortem human brains. J Neuro-Oncol 15:257–274.  https://doi.org/10.1080/13550280902973952 CrossRefGoogle Scholar
  96. Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B, Kumar M (2011) Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance. J Neuro-Oncol 17:26–40.  https://doi.org/10.1007/s13365-010-0003-4 CrossRefGoogle Scholar
  97. Lau CG, Zukin RS (2007) NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8:413–426.  https://doi.org/10.1038/nrn2153 CrossRefPubMedGoogle Scholar
  98. Lewczuk P, Ermann N, Andreasson U, Schultheis C, Podhorna J, Spitzer P, Maler JM, Kornhuber J, Blennow K, Zetterberg H (2018) Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer’s disease. Alzheimers Res Ther 10:71.  https://doi.org/10.1186/s13195-018-0404-9 CrossRefPubMedPubMedCentralGoogle Scholar
  99. Light GA, Swerdlow NR (2015) Future clinical uses of neurophysiological biomarkers to predict and monitor treatment response for schizophrenia. Ann N Y Acad Sci 1344:105–119.  https://doi.org/10.1111/nyas.12730 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Lim D, Iyer A, Ronco V, Grolla AA, Canonico PL, Aronica E, Genazzani AA (2013) Amyloid beta deregulates astroglia mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia 61:1134–1145.  https://doi.org/10.1002/glia.22502 CrossRefPubMedGoogle Scholar
  101. Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 453:869–878.  https://doi.org/10.1038/nature06976 CrossRefPubMedPubMedCentralGoogle Scholar
  102. Maki PM, Martin-Thormeyer E (2009) HIV, cognition and women. Neuropsychol Rev 19:204–214.  https://doi.org/10.1007/s11065-009-9093-2 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Maki PM, Rubin LH, Springer G, Seaberg EC, Sacktor N, Miller EN, Valcour V, Young MA, Becker JT, Martin EM, Neuropsychology Working Groups of the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study (2018) Differences in cognitive function between women and men with HIV. J Acquir Immune Defic Syndr 79:101–107.  https://doi.org/10.1097/QAI.0000000000001764 CrossRefPubMedGoogle Scholar
  104. Mansbach RS, Geyer MA, Braff DL (1998) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology 94:507–514CrossRefGoogle Scholar
  105. Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10:243–254CrossRefGoogle Scholar
  106. Mattsson N, Andreasson U, Zetterberg H, Blennow K, Alzheimer’s Disease Neuroimaging Initiative (2017) Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 74:557–566.  https://doi.org/10.1001/jamaneurol.2016.6117 CrossRefPubMedPubMedCentralGoogle Scholar
  107. McLaurin KA, Booze RM, Mactutus CF (2016) Progression of temporal processing deficits in the HIV-1 transgenic rat. Sci Rep 6:32831.  https://doi.org/10.1038/srep32831 CrossRefPubMedPubMedCentralGoogle Scholar
  108. McLaurin KA, Moran LM, Li H, Booze RM, Mactutus CF (2017a) A gap in time: extending our knowledge of temporal processing deficits in the HIV-1 transgenic rat. J NeuroImmune Pharmacol 12:171–179.  https://doi.org/10.1007/s11481-016-9711-8 CrossRefPubMedGoogle Scholar
  109. McLaurin KA, Booze RM, Mactutus CF (2017b) Temporal processing demands in the HIV-1 transgenic rat: amodal gating and implications for diagnostics. Int J Dev Neurosci 57:12–20.  https://doi.org/10.1016/j.ijdevneu.2016.11.004 CrossRefPubMedGoogle Scholar
  110. McLaurin KA, Booze RM, Mactutus CF (2017c) Selective developmental alterations in the HIV-1 transgenic rat: opportunities for diagnosis of pediatric HIV-1. J Neuro-Oncol 23:87–98.  https://doi.org/10.1007/s13365-016-0476-x CrossRefGoogle Scholar
  111. McLaurin KA, Booze RM, Mactutus CF, Fairchild AJ (2017d) Sex matters: robust sex differences in signal detection in the HIV-1 transgenic rat. Front Behav Neurosci 11:212.  https://doi.org/10.3389/fnbeh.2017.00212 CrossRefPubMedPubMedCentralGoogle Scholar
  112. McLaurin KA, Moran LM, Li H, Booze RM, Mactutus CF (2018a) The power of interstimulus interval for the assessment of temporal processing in rodents. J Vis Exp. (in press)Google Scholar
  113. McLaurin KA, Booze RM, Mactutus CF (2018b) Evolution of the HIV-1 transgenic rat: utility in assessing the progression of HIV-1-associated neurocognitive disorders. J Neuro-Oncol 24:229–245.  https://doi.org/10.1007/s13365-017-0544-x CrossRefGoogle Scholar
  114. McLaurin KA, Li H, Booze RM, Mactutus CF (2018c) Disruption of timing: NeuroHIV progression in the post-cART era. Sci Rep.  https://doi.org/10.1038/s41598-018-36822-1
  115. McLaurin KA, Cook AK, Li H, League AF, Mactutus CF, Booze RM (2018d) Synaptic connectivity in medium spiny neurons of the nucleus accumbens: a sex-dependent mechanism underlying apathy in the HIV-1 transgenic rat. Front Behav Neurosci 12:285.  https://doi.org/10.3389/fnbeh.2018.00285
  116. McLaurin KA, Li H, Booze RM, Fairchild AJ, Mactutus CF (2018e) Unraveling individual differences in the HIV-1 transgenic rat: therapeutic efficacy of methylphenidate. Sci Rep 8:136.  https://doi.org/10.1038/s41598-017-18300-2 CrossRefPubMedPubMedCentralGoogle Scholar
  117. Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, Wen TF, Lindsay RJ, Orellana L, Mildvan D, Bazner S, Streeck H, Alter G, Lifson JD, Carrington M, Bosch RJ, Robbins GK, Altfeld M (2009) Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV. Nat Med 15:955–959.  https://doi.org/10.1038/nm.2004 CrossRefPubMedPubMedCentralGoogle Scholar
  118. Melendez RI, Roman C, Capo-Velez CM, Lasalde-Dominicci JA (2016) Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J Neuro-Oncol 22:358–365.  https://doi.org/10.1007/s13365-015-0403-6 CrossRefGoogle Scholar
  119. Mellgren A, Price RW, Hagberg L, Rosengren L, Brew BJ, Gisslén M (2007) Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. Neurology 69:1536–1541.  https://doi.org/10.1212/01.wnl.0000277635.05973.55 CrossRefPubMedGoogle Scholar
  120. Merino-Serrais P, Benavides-Piccione R, Blazquez-Llorca L, Kastanauskaite A, Rábano A, Avila J, DeFelipe J (2013) The influence of phopho-τ on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease. Brain 136:1913–1928.  https://doi.org/10.1093/brain/awt088 CrossRefPubMedPubMedCentralGoogle Scholar
  121. Minassian A, Henry BL, Woods SP, Vaida F, Grant I, Geyer MA, Perry W (2013) Prepulse inhibition in HIV-associated neurocognitive disorders. J Int Neuropsychol Soc 19:709–717.  https://doi.org/10.1017/S1355617713000301 CrossRefPubMedPubMedCentralGoogle Scholar
  122. Moran LM, Booze RM, Mactutus CF (2013) Time and time again: temporal processing demands implicate perceptual and gating deficits in the HIV-1 transgenic rat. J NeuroImmune Pharmacol 8:988–997.  https://doi.org/10.1007/s11481-013-9472-6 CrossRefPubMedPubMedCentralGoogle Scholar
  123. Moya KL, Benowitz LI, Schneider GE, Allinquant B (1994) The amyloid precursor protein is developmentally regulated and correlated with synaptogenesis. Dev Biol 161:597–603.  https://doi.org/10.1006/dbio.1994.1055 CrossRefPubMedGoogle Scholar
  124. Myers CA, Brown PD (2006) Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol 24:1305–1309.  https://doi.org/10.1200/JCO.2005.04.6086 CrossRefGoogle Scholar
  125. Norgren N, Rosengren L, Stigbrand T (2003) Elevated neurofilament levels in neurological diseases. Brain Res 987:25–31CrossRefGoogle Scholar
  126. Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 87:9868–9872CrossRefGoogle Scholar
  127. Ortega M, Brier MR, Ances BM (2015) Effects of HIV and combination antiretroviral therapy on cortico-striatal functional connectivity. AIDS 29:703–712.  https://doi.org/10.1097/QAD.0000000000000611 CrossRefPubMedPubMedCentralGoogle Scholar
  128. Paris JJ, Singh HD, Carey AN, McLaughlin JP (2015) Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice. Behav Brain Res 291:209–218.  https://doi.org/10.1016/j.bbr.2015.05.021 CrossRefPubMedPubMedCentralGoogle Scholar
  129. Patton HK, Zhou ZH, Bubien JK, Benveniste EN, Benos DJ (2000) Gp120-induced alterations of human astrocyte function: Na(+)/H(+) exchange, K(+) conductance, and glutamate flux. Am J Phys Cell Phys 279:C700–C708.  https://doi.org/10.1152/ajpcell.2000.279.3.C700 CrossRefGoogle Scholar
  130. Peluso MJ, Meyerhoff DJ, Price RW, Peterson J, Lee E, Young AC, Walter R, Fuchs D, Brew BJ, Cinque P, Robertson K, Hagberg L, Zetterberg H, Gisslén M, Spudich S (2013) Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. J Infect Dis 207:1703–1712.  https://doi.org/10.1093/infdis/jit088 CrossRefPubMedPubMedCentralGoogle Scholar
  131. Peterson J, Gisslén M, Zetterberg H, Fuchs D, Shacklett BL, Hagberg L, Yiannoutsos CT, Spudich SS, Price RW (2014) Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection. PLoS One 9:e116081.  https://doi.org/10.1371/journal.pone.0116081 CrossRefPubMedPubMedCentralGoogle Scholar
  132. Pickney LA (1976) Inhibition of the startle reflex in the rat by prior tactile stimulation. Anim Learn Behav 4:476–472.  https://doi.org/10.1093/jn/126.3.618 CrossRefGoogle Scholar
  133. Power C, Selnes OA, Grim JA, McArthur JC (1995) HIV dementia scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol 8:273–278CrossRefGoogle Scholar
  134. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (2006) Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26:7212–7221.  https://doi.org/10.1523/JNEUROSCI.1450-06.2006 CrossRefPubMedGoogle Scholar
  135. Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC (2010) Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 28:595–599.  https://doi.org/10.1038/nbt.1641 CrossRefPubMedPubMedCentralGoogle Scholar
  136. Rojas JC, Karydas A, Bang J, Tsai RM, Blennow K, Liman V, Kramer JH, Rosen H, Miller BL, Zetterberg H, Boxer AL (2016) Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Ann Clin Transl Neurol 3:216–225.  https://doi.org/10.1002/acn3.290 CrossRefPubMedPubMedCentralGoogle Scholar
  137. Romley JA, Juday T, Solomon MD, Seekins D, Brookmeyer R, Goldman DP (2014) Early HIV treatment led to life expectancy gains valued at $80 billion for people infected in 1996-2009. Health Aff (Millwood) 33:370–377.  https://doi.org/10.1377/hlthaff.2013.0623 CrossRefGoogle Scholar
  138. Roscoe RF Jr, Mactutus CF, Booze RM (2014) HIV-1 transgenic female rat: synaptodendritic alterations of medium spiny neurons in the nucleus accumbens. J NeuroImmune Pharmacol 9:642–653.  https://doi.org/10.1007/s11481-014-9555-z CrossRefPubMedPubMedCentralGoogle Scholar
  139. Rowson SA, Harrell CS, Bekhbat M, Gangavelli A, Wu MJ, Kelly SD, Reddy R, Neigh GN (2016) Neuroinflammation and behavior in HIV-1 transgenic rats exposed to chronic adolescent stress. Front Psychiatry 7:102.  https://doi.org/10.3389/fpsyt.2016.00102 CrossRefPubMedPubMedCentralGoogle Scholar
  140. Royal W 3rd, Zhang L, Guo M, Jones O, Davis H, Bryant JL (2012) Immune activation, viral gene product expression and neurotoxicity in the HIV-1 transgenic rat. J Neuroimmunol 247:16–24.  https://doi.org/10.1016/j.jneuroim.2012.03.015 CrossRefPubMedPubMedCentralGoogle Scholar
  141. Royal W, Cherner M, Burdo TH, Umlauf A, Letendre SL, Jumare J, Abimiku A, Alabi P, Alkali N, Bwala S, Okwuasaba K, Eyzaguirre LM, Akolo C, Guo M, Williams KC, Blattner WA (2016) Associations between cognition, gender and monocyte activation among HIV infected individuals in Nigeria. PLoS One 11:e0147182.  https://doi.org/10.1371/journal.pone.0147182 CrossRefPubMedPubMedCentralGoogle Scholar
  142. Rucker DD, McShane BB, Preacher KJ (2015) A researcher’s guide to regression, dichotomization, and median splits of continuous variables. J Consum Psychol 4:666–678.  https://doi.org/10.1016/j.jcps.2015.04.004 CrossRefGoogle Scholar
  143. Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes OA, Musisi S, Robertson K, McArthur JC, Ronald A, Katabira E (2005) The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS 19:1367–1374PubMedGoogle Scholar
  144. Sakamoto M, Marcotte TD, Umlauf A, Franklin D, Heaton RK, Ellis RJ, Letendre S, Alexander T, McCutchan JA, Morgan EE, Woods SP, Collier AC, Marra CM, Clifford DB, Gelman BB, McArthur JC, Morgello S, Simpson D, Grant I, CHARTER Group (2013) Concurrent classification accuracy of the HIV dementia scale for HIV-associated neurocognitive disorders in the CHARTER cohort. J Acquir Immune Defic Syndr 62:36–42.  https://doi.org/10.1097/QAI.0b013e318278ffa4 CrossRefPubMedPubMedCentralGoogle Scholar
  145. Schwarzkopf SB, McCoy L, Smith DA, Boutros NN (1993) Test-retest reliability of prepulse inhibition of the acoustic startle response. Biol Psychiatry 34:896–900CrossRefGoogle Scholar
  146. Sinharay S, Lee D, Shah S, Muthusamy S, Papadakis GZ, Zhang X, Maric D, Reid WC, Hammoud DA (2017) Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV. Nucl Med Biol 55:27–33.  https://doi.org/10.1016/j.nucmedbio.2017.08.004 CrossRefPubMedPubMedCentralGoogle Scholar
  147. Smit M, Binkman K, Geerlings S, Smit C, Thyagarajan K, Sighem AV, de Wolf F, Hallett TB, ATHENA Observational Cohort (2015) Future challenges for clinical care of an ageing population infected with HIV: a modelling study. Lancet Infect Dis 15:810–818.  https://doi.org/10.1016/S1473-3099(15)00056-0 CrossRefPubMedPubMedCentralGoogle Scholar
  148. Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, Filippini N, Wakins KE, Toro R, Laird AR, Beckmann CF (2009) Correspondence of the brain’s functional architecture during activation and rest. Proc Natl Acad Sci U S A 106:13040–13045.  https://doi.org/10.1073/pnas.0905267106 CrossRefPubMedPubMedCentralGoogle Scholar
  149. Steinacker P, Semler E, Anderl-Straub S, Diehl-Schmid J, Schroeter ML, Uttner I, Foerstl H, Landwehrmeyer B, von Arnim CA, Kassubek J, Oeckl P, Huppertz HJ, Fassbender K, Fliessbach K, Prudlo J, Robmeier C, Kornhuber J, Schneider A, Volk AE, Lauer M, Danek A, Ludolph AC, Otto M, FTLDc Study Group (2017) Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias. Neurology 88:961–969.  https://doi.org/10.1212/WNL.0000000000003688 CrossRefPubMedGoogle Scholar
  150. Steinbrink F, Evers S, Buerke B, Young P, Arendt G, Koutsilieri E, Reichelt D, Lohmann H, Husstedt IW, German Competence Network HIV/AIDS (2013) Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration. Eur J Neurol 20:420–428.  https://doi.org/10.1111/ene.12006 CrossRefPubMedGoogle Scholar
  151. Strimbu K, Tavel JA (2010) What are biomarkers? Curr Opin HIV AIDS 5:463–466.  https://doi.org/10.1097/COH.0b013e32833ed177 CrossRefPubMedPubMedCentralGoogle Scholar
  152. Taber MT, Fibiger HC (1995) Electrical stimulation of the prefrontal cortex increases dopamine release in the nucleus accumbens of the rat: modulation by metabotropic glutamate receptors. J Neurosci 15:3896–3904CrossRefGoogle Scholar
  153. Teeraananchai S, Kerr SJ, Amin J, Ruxrungtham K, Law MG (2017) Life expectancy of HIV-positive people after starting combination antiretroviral therapy: a meta-analysis. HIV Med 18:256–266.  https://doi.org/10.1111/hiv.12421 CrossRefPubMedGoogle Scholar
  154. Thomas JB, Brier MR, Snyder AZ, Vaida FF, Ances BM (2013) Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity. Neurology 80:1186–1193.  https://doi.org/10.1212/WNL.0b013e318288792b CrossRefPubMedPubMedCentralGoogle Scholar
  155. Thomas JB, Brier MR, Ortega M, Benzinger TL, Ances BM (2015) Weighted brain networks in disease: centrality and entropy in human immunodeficiency virus and aging. Neurobiol Aging 36:401–412.  https://doi.org/10.1016/j.neurobiolaging.2014.06.019 CrossRefPubMedGoogle Scholar
  156. Thulborn KR, Waterton JC, Matthews PM, Radda GK (1982) Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim Biophys Acta 714:265–270CrossRefGoogle Scholar
  157. Toledo JB, Shaw LM, Trojanowski JQ (2013) Plasma amyloid beta measurements—a desired but elusive Alzheimer’s disease biomarker. Alzheimers Res Ther 5:8.  https://doi.org/10.1186/alzrt162 CrossRefPubMedPubMedCentralGoogle Scholar
  158. Ueki A, Goto K, Sato N, Iso H, Morita Y (2006) Prepulse inhibition of acoustic startle response in mild cognitive impairment and mild dementia of Alzheimer type. Psychiatry Clin Neurosci 60:55–62.  https://doi.org/10.1111/j.1440-1819.2006.01460.x CrossRefPubMedGoogle Scholar
  159. Ulrich D (2015) Amyloid-β impairs synaptic inhibition via GABA(A) receptor endocytosis. J Neurosci 35:9205–9210.  https://doi.org/10.1523/JNEUROSCI.0950-15.2015 CrossRefPubMedGoogle Scholar
  160. UNAIDS (2014) People aged 50 years and older. Available online at: http://www.unaids.org/sites/default/files/media_asset/12_Peopleaged50yearsandolder.pdf
  161. UNAIDS (2017) Fact sheet. Available online at: http://www.unaids.org/sites/ default/files/media_asset/ UNAIDS_FactSheet_en.pdf
  162. Varga E, Juhász G, Bozsό Z, Penke B, Fϋlop L, Szegedi V (2015) Amyloid-β1-42 disrupts synaptic plasticity by altering glutamate recycling at the synapse. J Alzheimers Dis 45:449–456.  https://doi.org/10.3233/JAD-142367 CrossRefPubMedGoogle Scholar
  163. Ventura N, Douw L, Correa DG, Netto TM, Cabral RF, Lopes FCR, Gasparetto EL (2018) Increased posterior cingulate cortex efficiency may predict cognitive impairment in asymptomatic HIV patients. Neuroradiol J 31:372–378.  https://doi.org/10.1177/1971400918782327 CrossRefPubMedGoogle Scholar
  164. Wang Z, Pekarskaya O, Bencheikh M, Chao W, Gelbard HA, Ghorpade A, Rothstein JD, Volsky DJ (2003) Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120. Virology 312:60–73CrossRefGoogle Scholar
  165. Wang X, Foryt P, Ochs R, Chung J, Wu Y, Parrish T, Ragin AB (2011) Abnormalities in resting-state functional connectivity in early human immunodeficiency virus infection. Brain Connect 1:207–217.  https://doi.org/10.1089/brain.2011.0016 CrossRefPubMedPubMedCentralGoogle Scholar
  166. Wang H, Li R, Zhou Y, Wang Y, Cui J, Nguchu BA, Qiu B, Wang X, Li H (2018a) Altered cerebro-cerebellum resting-state functional connectivity in HIV-infected male patients. J Neurovirol.  https://doi.org/10.1007/s13365-018-0649-x
  167. Wang P, Li J, Wang X, Thapa D, Wu GY (2018b) Asymptomatic human immunodeficiency virus vertical transmitted adolescents’ brain functional changes: based on resting-state functional magnetic resonance imaging. AIDS Res Hum Retrovir 34:699–704.  https://doi.org/10.1089/AID.2017.0267 CrossRefPubMedGoogle Scholar
  168. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 72:1858–1862CrossRefGoogle Scholar
  169. Weyer SW, Zagrebelsky M, Herrmann U, Hick M, Ganss L, Gobbert J, Gruber M, Altmann C, Korte M, Deller T, Muller UC (2014) Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression. Acta Neuropathol Commun 2:36.  https://doi.org/10.1186/2051-5960-2-36 CrossRefPubMedPubMedCentralGoogle Scholar
  170. WHO International Programme on Chemical Safety Biomarkers in Risk Assessment: Validity and Validation. 2001. Retrieved from http://www.inchem.org/documents/ehc/ehc/ehc222.htm
  171. Woods SP, Morgan EE, Marquie-Beck J, Carey CL, Grant I, Letendre SL, The HIV Neurobehavioral Research Center Group (2006) Markers of macrophage activation and axonal injury are associated with prospective memory in HIV-1 disease. Cogn Behav Neurol 19:217–221.  https://doi.org/10.1097/01.wnn.0000213916.10514.57 CrossRefPubMedPubMedCentralGoogle Scholar
  172. Woods SP, Moore DJ, Weber E, Grant I (2009) Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychol Rev 19:152–168.  https://doi.org/10.1007/s11065-009-9102-5 CrossRefPubMedPubMedCentralGoogle Scholar
  173. Yu Y, Run X, Liang Z, Li Y, Liu F, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases. J Neurochem 108:1480–1494.  https://doi.org/10.1111/j.1471-4159.2009.05882.x CrossRefPubMedPubMedCentralGoogle Scholar
  174. Yuan A, Rao MV, Sasaki T, Chen Y, Kumar A, Veeranna, Liem RK, Eyer J, Peterson AC, Julien JP, Nixon RA (2006) Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. J Neurosci 26:10006–10019.  https://doi.org/10.1523/JNEUROSCI.2580-06.2006 CrossRefPubMedGoogle Scholar
  175. Yuan A, Rao MV, Veeranna NRA (2012) Neurofilaments at a glance. J Cell Sci 125:3257–3263CrossRefGoogle Scholar
  176. Yuan L, Qiao L, Wei F, Yin J, Liu L, Ji Y, Smith D, Li N, Chen D (2013) Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China. J Neuro-Oncol 19:144–149.  https://doi.org/10.1007/s13365-013-0150-5 CrossRefGoogle Scholar
  177. Yuan A, Sershen H, Veeranna BBS, Kumar A, Hashim A, Berg M, Lee J, Sato Y, Rao MV, Mohan PS, Dyakin V, Julien JP, Lee VM, Nixon RA (2015) Neurofilament subunits are integral components of synapses and modulate neurotransmission and behavior in vivo. Mol Psychiatry 20:986–994.  https://doi.org/10.1038/mp.2015.45 CrossRefPubMedPubMedCentralGoogle Scholar
  178. Yuan A, Nixon RA (2016) Specialized roles of neurofilament proteins in synapses: relevance to neuropsychiatric disorders. Brain Res Bull 126:334–346.  https://doi.org/10.1016/j.brainresbull.2016.09.002 CrossRefPubMedPubMedCentralGoogle Scholar
  179. Yuan A, Veeranna SH, Basavarajappa BS, Smiley JF, Hashim A, Bleiwas C, Berg M, Guifoyle DN, Subbanna S, Darji S, Kumar A, Rao MV, Wilson DA, Julien J, Javitt DC, Nixon RA (2018) Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors. Transl Psychiatry 8:167.  https://doi.org/10.1038/s41398-018-0194-7 CrossRefPubMedPubMedCentralGoogle Scholar
  180. Zang Y, Jiang T, Lu Y, He Y, Tian L (2004) Regional homogeneity approach to fMRI data analysis. Neuroimage 22:394–400.  https://doi.org/10.1016/j.neuroimage.2003.12.030 CrossRefPubMedGoogle Scholar
  181. Zempel H, Thies E, Madelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30:11938–11950.  https://doi.org/10.1523/JNEUROSCI.2357-10.2010 CrossRefPubMedGoogle Scholar
  182. Zipursky AR, Gogolishvili D, Rueda S, Brunetta J, Carvalhal A, McCombe JA, Gill MJ, Rachlis A, Rosenes R, Arbess G, Marcotte T, Rourke SB (2013) Evaluation of brief screening tools for neurocognitive impairment in HIV/AIDS:a systematic review of the literature. AIDS 27:2385–2401.  https://doi.org/10.1097/QAD.0b013e328363bf56 CrossRefPubMedPubMedCentralGoogle Scholar
  183. Zhang J, Forkstam C, Engel JA, Svensson L (2000) Role of dopamine in prepulse inhibition of acoustic startle. Psychopharmacology 149:181–188CrossRefGoogle Scholar
  184. Zou C, Crux S, Marinesco S, Montagna E, Sgobio C, Shi Y, Shi S, Zhu K, Dorostkar MM, Muller UC, Herms J (2016) Amyloid precursor protein maintains constitutive and adaptive plasticity of dendritic spines in adult brain by regulating D-serine homeostasis. EMBO J 35:2213–2222.  https://doi.org/10.15252/embj.201694085 CrossRefPubMedPubMedCentralGoogle Scholar
  185. Zweig MH, Campbell G (1993) Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 39:561–577PubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2019

Authors and Affiliations

  • Kristen A. McLaurin
    • 1
  • Rosemarie M. Booze
    • 1
  • Charles F. Mactutus
    • 1
  1. 1.Program in Behavioral Neuroscience, Department of PsychologyUniversity of South CarolinaColumbiaUSA

Personalised recommendations