Abstract
Our objective was to predict HIV-associated neurocognitive disorder (HAND) in HIV-infected people using plasma neuronal extracellular vesicle (nEV) proteins, clinical data, and machine learning. We obtained 60 plasma samples from 38 women and 22 men, all with HIV infection and 40 with HAND. All underwent neuropsychological testing. nEVs were isolated by immunoadsorption with neuron-specific L1CAM antibody. High-mobility group box 1 (HMGB1), neurofilament light (NFL), and phosphorylated tau-181 (p-T181-tau) proteins were quantified by ELISA. Three different computational algorithms were performed to predict cognitive impairment using clinical data and nEV proteins. Of the 3 different algorithms, support vector machines performed the best. Applying 4 different models of clinical data with 3 nEV proteins, we showed that selected clinical data and HMGB1 plus NFL best predicted cognitive impairment with an area under the curve value of 0.82. The most important features included CD4 count, HMGB1, and NFL. Previous published data showed nEV p-T181-tau was elevated in Alzheimer’s disease (AD), and in this study, p-T181-tau had no importance in assessing HAND but may actually differentiate it from AD. Machine learning can access data without programming bias. Identifying a few nEV proteins plus key clinical variables can better predict neuronal damage. This approach may differentiate other neurodegenerative diseases and determine recovery after therapies are identified.
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References
Anderson AE, Jones JD, Thaler NS, Kuhn TP, Singer EJ, Hinkin CH (2018) Intraindividual variability in neuropsychological performance predicts cognitive decline and death in HIV. Neuropsychology 32:966–972
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen 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
Bridel C, van Wieringen WN, Zetterberg H, Tijms BM, Teunissen CE, the NFLG, Alvarez-Cermeno JC, Andreasson U, Axelsson M, Backstrom DC, Bartos A, Bjerke M, Blennow K, Boxer A, Brundin L, Burman J, Christensen T, Fialova L, Forsgren L, Frederiksen JL, Gisslen M, Gray E, Gunnarsson M, Hall S, Hansson O, Herbert MK, Jakobsson J, Jessen-Krut J, Janelidze S, Johannsson G, Jonsson M, Kappos L, Khademi M, Khalil M, Kuhle J, Landen M, Leinonen V, Logroscino G, Lu CH, Lycke J, Magdalinou NK, Malaspina A, Mattsson N, Meeter LH, Mehta SR, Modvig S, Olsson T, Paterson RW, Perez-Santiago J, Piehl F, Pijnenburg YAL, Pyykko OT, Ragnarsson O, Rojas JC, Romme Christensen J, Sandberg L, Scherling CS, Schott JM, Sellebjerg FT, Simone IL, Skillback T, Stilund M, Sundstrom P, Svenningsson A, Tortelli R, Tortorella C, Trentini A, Troiano M, Turner MR, van Swieten JC, Vagberg M, Verbeek MM, Villar LM, Visser PJ, Wallin A, Weiss A, Wikkelso C, Wild EJ (2019) Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurology 76:1035–1048
Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK, Group H (2004) Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26:307–319
Chettimada S, Lorenz DR, Misra V, Dillon ST, Reeves RK, Manickam C, Morgello S, Kirk GD, Mehta SH, Gabuzda D (2018) Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy. Sci Rep 8:7227
Dalvi P, Sun B, Tang N, Pulliam L (2017) Immune activated monocyte exosomes alter microRNAs in brain endothelial cells and initiate an inflammatory response through the TLR4/MyD88 pathway. Sci Rep 7:9954
Dayon L, Wojcik J, Nunez Galindo A, Corthesy J, Cominetti O, Oikonomidi A, Henry H, Migliavacca E, Bowman GL, Popp J (2017) Plasma proteomic profiles of cerebrospinal fluid-defined Alzheimer’s disease pathology in older adults. J Alzheimers Dis 60:1641–1652
Du Pasquier RA, Jilek S, Kalubi M, Yerly S, Fux CA, Gutmann C, Cusini A, Gunthard HF, Cavassini M, Vernazza PL, Swiss HIVCS (2013) Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy. AIDS 27:203–210
Eden A, Marcotte TD, Heaton RK, Nilsson S, Zetterberg H, Fuchs D, Franklin D, Price RW, Grant I, Letendre SL, Gisslen M (2016) Increased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment. PLoS One 11:e0157160
Fang P, Schachner M, Shen YQ (2012) HMGB1 in development and diseases of the central nervous system. Mol Neurobiol 45:499–506
Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, Kapogiannis D (2015) Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 85:40–47
Gougeon ML, Poirier-Beaudouin B, Durant J, Lebrun-Frenay C, Saidi H, Seffer V, Ticchioni M, Chanalet S, Carsenti H, Harvey-Langton A, Laffon M, Cottalorda J, Pradier C, Dellamonica P, Vassallo M (2017) HMGB1/anti-HMGB1 antibodies define a molecular signature of early stages of HIV-associated neurocognitive disorders (HAND). Heliyon 3:e00245
Gupta A, Pulliam L (2014) Exosomes as mediators of neuroinflammation. J Neuroinflammation 11:68
Hu G, Yang L, Cai Y, Niu F, Mezzacappa F, Callen S, Fox HS, Buch S (2016) Emerging roles of extracellular vesicles in neurodegenerative disorders: focus on HIV-associated neurological complications. Cell Death Dis 7:e2481
Kapogiannis D, Mustapic M, Shardell MD, Berkowitz ST, Diehl TC, Spangler RD, Tran J, Lazaropoulos MP, Chawla S, Gulyani S, Eitan E, An Y, Huang CW, Oh ES, Lyketsos CG, Resnick SM, Goetzl EJ, Ferrucci L (2019) Association of extracellular vesicle biomarkers with Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurology 73:1340–1351
McGuire JL, Gill AJ, Douglas SD, Kolson DL, group CHA-RTER (2015) Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neuro-Oncol 21:439–448
Pemberton LA, Brew BJ (2001) Cerebrospinal fluid S-100beta and its relationship with AIDS dementia complex. J Clin Virol 22:249–253
Peterson J, Gisslen 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
Price RW, Peterson J, Fuchs D, Angel TE, Zetterberg H, Hagberg L, Spudich S, Smith RD, Jacobs JM, Brown JN, Gisslen M (2013) Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection. J NeuroImmune Pharmacol 8:1147–1158
Pulliam L, Sun B, Mustapic M, Chawla S, Kapogiannis D (2019) Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer’s disease. J Neuro-Oncol 25:702–709
Santangelo R, Dell’Edera A, Sala A, Cecchetti G, Masserini F, Caso F, Pinto P, Leocani L, Falautano M, Passerini G, Martinelli V, Comi G, Perani D, Magnani G (2019) The CSF p-tau181/Abeta42 ratio offers a good accuracy "in vivo" in the differential diagnosis of Alzheimer’s dementia. Curr Alzheimer Res 16:587–595
Sun B, Dalvi P, Abadjian L, Tang N, Pulliam L (2017) Blood neuron-derived exosomes as biomarkers of cognitive impairment in HIV. AIDS 31:F9–F17
Sun B, Fernandes N, Pulliam L (2019) Profile of neuronal exosomes in HIV cognitive impairment exposes sex differences. AIDS 33:1683–1692
Tang N, Sun B, Gupta A, Rempel H, Pulliam L (2016) Monocyte exosomes induce adhesion molecules and cytokines via activation of NF-kappaB in endothelial cells. FASEB J 30:3097–3106
Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579
Tu W, Chen PA, Koenig N, Gomez D, Fujiwara E, Gill MJ, Kong L, Power C (2020) Machine learning models reveal neurocognitive impairment type and prevalence are associated with distinct variables in HIV/AIDS. J Neuro-Oncol 26:41–51
Yilmaz A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2008) Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy. J Acquir Immune Defic Syndr 47:168–173
Funding
This study was supported by the NIH (LP R21MH112483).
Participant plasma samples were funded by shared resources from NIMH and NINDS by the following grants: Manhattan HIV Brain Bank (MHBB): U24MH10093, Texas NeuroAIDS Research Center (TNRC): U24MH100930, National Neurological AIDS Bank (NNAB): U24MHw100929, California NeuroAIDS Tissue Network (CNTN): U24MH100928. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the National NeuroAIDS Tissue Consortium (NNTC) or NIH. The authors also acknowledge the HIV Neurobehavioral Research Center (HNRC) supported by public funding from the National Institutes of Health (NIH), the State of California, and other sources (NIMH/CSPAR Award Number P30MH062512) for samples used in this study.
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Pulliam, L., Liston, M., Sun, B. et al. Using neuronal extracellular vesicles and machine learning to predict cognitive deficits in HIV. J. Neurovirol. 26, 880–887 (2020). https://doi.org/10.1007/s13365-020-00877-6
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DOI: https://doi.org/10.1007/s13365-020-00877-6