Abstract
Simian immunodeficiency virus (SIV)-infected macaque is a widely used model to study human immunodeficiency virus. The purpose of the study is to discover the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) changes in SIV-infected macaques. Seven rhesus macaques were involved in the longitudinal MRI scans: (1) baseline (healthy state); (2) SIV infection stage (12 weeks after SIV inoculation). ALFF and fALFF were subsequently computed and compared to ascertain the changes caused by SIV infection. Whole-brain correlation analysis was further used to explore the possible associations between ALFF/fALFF values and immune status parameters (CD4+ T cell counts, CD4/CD8 ratio and virus load). Compared with the baseline, macaques in SIV infection stage displayed strengthened ALFF values in left precuneus, postcentral gyrus, and temporal gyrus, and weakened ALFF values in orbital gyrus and inferior temporal gyrus. Meanwhile, increased fALFF values were found in left superior frontal gyrus, right precentral gyrus, and superior temporal gyrus, while decreased fALFF values existed in left hippocampus, left caudate, and right inferior frontal gyrus. Furthermore, ALFF and fALFF values in several brain regions showed significant relationships with CD4+ T cell counts, CD4/CD8 ratio, and plasma virus load. Our findings could promote the understanding of neuroAIDS caused by HIV infection, which may provide supplementary evidences for the future therapy study in SIV model.
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References
Abidin AZ, AM DS, 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
Aiello M, Salvatore E, Cachia A, Pappata S, Cavaliere C, Prinster A, Nicolai E, Salvatore M, Baron JC, Quarantelli M (2015) Relationship between simultaneously acquired resting-state regional cerebral glucose metabolism and functional MRI: a PET/MR hybrid scanner study. Neuroimage 113:111–121
Ann HW, Jun S, Shin NY, Han S, Ahn JY, Ahn MY, Jeon YD, Jung IY, Kim MH, Jeong WY, Ku NS, Kim JM, Smith DM, Choi JY (2016) Characteristics of resting-state functional connectivity in HIV-associated neurocognitive disorder. PLoS One 11:e0153493
Bernier M, Croteau E, Castellano CA, Cunnane SC, Whittingstall K (2017) Spatial distribution of resting-state BOLD regional homogeneity as a predictor of brain glucose uptake: a study in healthy aging. Neuroimage 150:14–22
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
Chang L, Speck O, Miller EN, Braun J, Jovicich J, Koch C, Itti L, Ernst T (2001) Neural correlates of attention and working memory deficits in HIV patients. Neurology 57:1001–1007
Cloak CC, Chang L, O'Neil SP, Ernst TM, Anderson DC, Donahoe RM (2011) Neurometabolite abnormalities in simian immunodeficiency virus-infected macaques with chronic morphine administration. J NeuroImmune Pharmacol 6:371–380
Cysique LA, Brew BJ (2011) Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neuro-Oncol 17:176–183
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
Ernst T, Chang L, Jovicich J, Ames N, Arnold S (2002) Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients. Neurology 59:1343–1349
Fox MD, Raichle ME (2007) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8:700–711
Gonzalez RG, Fell R, He J, Campbell J, Burdo TH, Autissier P, Annamalai L, Taheri F, Parker T, Lifson JD, Halpern EF, Vangel M, Masliah E, Westmoreland SV, Williams KC, Ratai EM (2018) Temporal/compartmental changes in viral RNA and neuronal injury in a primate model of NeuroAIDS. PLoS One 13:e0196949
Greco JB, Westmoreland SV, Ratai EM, Lentz MR, Sakaie K, He J, Sehgal PK, Masliah E, Lackner AA, Gonzalez RG (2004) In vivo 1H MRS of brain injury and repair during acute SIV infection in the macaque model of neuroAIDS. Magn Reson Med 51:1108–1114
Greicius MD, Srivastava G, Reiss AL, Menon V (2004) Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 101:4637–4642
Guha A, Wang L, Tanenbaum A, Esmaeili-Firidouni P, Wendelken 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
Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, Cahn P, Fischl MA, Gatell JM, Hirsch MS, Jacobsen DM, Montaner JS, Richman DD, Yeni PG, Volberding PA, International AS-USA (2008) Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 300:555–570
Haynes B, Pitkanen M, Kulasegaram R, Casey S, Schutte M, Towgood K, Peters B, Barker G, Kopelman M (2018) HIV: ageing, cognition and neuroimaging at 4-year follow-up. HIV Med 19:376–385
Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C, Group H (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neuro-Oncol 17:3–16
Huang M, Lu S, Yu L, Li L, Zhang P, Hu J, Zhou W, Hu S, Wei N, Huang J, Weng J, Xu Y (2017) Altered fractional amplitude of low frequency fluctuation associated with cognitive dysfunction in first-episode drug-naive major depressive disorder patients. BMC Psychiatry 17:11
Janssen MA, Meulenbroek O, Steens SC, Goraj B, Bosch M, Koopmans PP, Kessels RP (2015) Cognitive functioning, wellbeing and brain correlates in HIV-1 infected patients on long-term combination antiretroviral therapy. AIDS 29:2139–2148
Janssen MAM, Hinne M, Janssen RJ, van Gerven MA, Steens SC, Goraj 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
Kojima T, Onoe H, Hikosaka K, Tsutsui K, Tsukada H, Watanabe M (2009) Default mode of brain activity demonstrated by positron emission tomography imaging in awake monkeys: higher rest-related than working memory-related activity in medial cortical areas. J Neurosci 29:14463–14471
Kumar AM, Borodowsky I, Fernandez B, Gonzalez L, Kumar M (2007) Human immunodeficiency virus type 1 RNA levels in different regions of human brain: quantification using real-time reverse transcriptase-polymerase chain reaction. J Neuro-Oncol 13:210–224
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 different regions of postmortem human brains. J Neuro-Oncol 15:257–274
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
Langford SE, Ananworanich J, Cooper DA (2007) Predictors of disease progression in HIV infection: a review. AIDS Res Ther 4:11
Lentz MR, Kim WK, Lee V, Bazner S, Halpern EF, Venna N, Williams K, Rosenberg ES, Gonzalez RG (2009) Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection. Neurology 72:1465–1472
Lentz MR, Westmoreland SV, Lee V, Ratai EM, Halpern EF, Gonzalez RG (2008) Metabolic markers of neuronal injury correlate with SIV CNS disease severity and inoculum in the macaque model of neuroAIDS. Magn Reson Med 59:475–484
Li C, Zhang X, Komery A, Li Y, Novembre FJ, Herndon JG (2011) Longitudinal diffusion tensor imaging and perfusion MRI investigation in a macaque model of neuro-AIDS: a preliminary study. Neuroimage 58:286–292
Li CX, Herndon JG, Novembre FJ, Zhang X (2015) A longitudinal magnetization transfer imaging evaluation of brain injury in a macaque model of neuroAIDS. AIDS Res Hum Retrovir 31:335–341
Li Y, Jing B, Liu H, Li Y, Gao X, Li Y, Mu B, Yu H, Cheng J, Barker PB, Wang H, Han Y (2017) Frequency-dependent changes in the amplitude of low-frequency fluctuations in mild cognitive impairment with mild depression. J Alzheimers Dis 58:1175–1187
Liu H, Xiao QH, Liu JB, Li JL, Zhou L, Xian QY, Wang Y, Zhang J, Wang X, Ho WZ, Zhuang K (2016) SIV infection impairs the central nervous system in Chinese rhesus macaques. J NeuroImmune Pharmacol 11:592–600
Mallard J, Williams KC (2018) Animal models of HIV-associated disease of the central nervous system. Handb Clin Neurol 152:41–53
Mantini D, Gerits A, Nelissen K, Durand JB, Joly O, Simone L, Sawamura H, Wardak C, Orban GA, Buckner RL, Vanduffel W (2011) Default mode of brain function in monkeys. J Neurosci 31:12954–12962
Marcondes MC, Burudi EM, Huitron-Resendiz S, Sanchez-Alavez M, Watry D, Zandonatti M, Henriksen SJ, Fox HS (2001) Highly activated CD8(+) T cells in the brain correlate with early central nervous system dysfunction in simian immunodeficiency virus infection. J Immunol 167:5429–5438
Mateo C, Knutsen PM, Tsai PS, Shih AY, Kleinfeld D (2017) Entrainment of arteriole vasomotor fluctuations by neural activity is a basis of blood-oxygenation-level-dependent “resting-state” connectivity. Neuron 96:936–948 e3
Matsui T, Murakami T, Ohki K (2016) Transient neuronal coactivations embedded in globally propagating waves underlie resting-state functional connectivity. Proc Natl Acad Sci U S A 113:6556–6561
Mbugua KK, Holmes MJ, Cotton MF, Ratai EM, Little F, Hess AT, Dobbels E, Van der Kouwe AJ, Laughton B, Meintjes EM (2016) HIV-associated CD4+/CD8+ depletion in infancy is associated with neurometabolic reductions in the basal ganglia at age 5 years despite early antiretroviral therapy. AIDS 30:1353–1362
McArthur JC, Brew BJ, Nath A (2005) Neurological complications of HIV infection. Lancet Neurol 4:543–555
McArthur JC, McDermott MP, McClernon D, St Hillaire C, Conant K, Marder K, Schifitto G, Selnes OA, Sacktor N, Stern Y, Albert SM, Kieburtz K, deMarcaida JA, Cohen B, Epstein LG (2004) Attenuated central nervous system infection in advanced HIV/AIDS with combination antiretroviral therapy. Arch Neurol 61:1687–1696
Navia BA, Jordan BD, Price RW (1986) The AIDS dementia complex: I. Clinical features. Ann Neurol 19:517–524
Ni L, Liu R, Yin Z, Zhao H, Nedelska Z, Hort J, Zhou F, Wu W, Zhang X, Li M, Yu H, Zhu B, Xu Y, Zhang B (2016) Aberrant spontaneous brain activity in patients with mild cognitive impairment and concomitant lacunar infarction: a resting-state functional MRI study. J Alzheimers Dis 50:1243–1254
Paul R, Prasitsuebsai W, Jahanashad N, Puthanakit T, Thompson P, Aurpibul L, Hansudewechakul R, Kosalaraksa P, Kanjanavanit S, Ngampiyaskul C, Luesomboon W, Lerdlum S, Pothisri M, Visrutaratna P, Valcour V, Nir TM, Saremi A, Kerr S, Ananworanich J, Group PS (2017). Structural neuroimaging and neuropsychologic signatures of vertically acquired HIV. Pediatr Infect Dis J, 1
Rao JS, Ma M, Zhao C, Zhang AF, Yang ZY, Liu Z, Li XG (2014) Fractional amplitude of low-frequency fluctuation changes in monkeys with spinal cord injury: a resting-state fMRI study. Magn Reson Imaging 32:482–486
Ratai EM, Pilkenton SJ, Greco JB, Lentz MR, Bombardier JP, Turk KW, He J, Joo CG, Lee V, Westmoreland S, Halpern E, Lackner AA, Gonzalez RG (2009) In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain. BMC Neurosci 10:63
Rohlfing T, Kroenke CD, Sullivan EV, Dubach MF, Bowden DM, Grant KA, Pfefferbaum A (2012) The INIA19 template and NeuroMaps atlas for primate brain image parcellation and spatial normalization. Front Neuroinform 6:27
Sanchez-Vives MV, Massimini M, Mattia M (2017) Shaping the default activity pattern of the cortical network. Neuron 94:993–1001
Scheller C, Sopper S, Jenuwein M, Neuen-Jacob E, Tatschner T, Grunblatt E, ter Meulen V, Riederer P, Koutsilieri E (2005) Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation. J Neurochem 95:377–387
Sun Y, Dai Z, Li Y, Sheng C, Li H, Wang X, Chen X, He Y, Han Y (2016) Subjective cognitive decline: mapping functional and structural brain changes—a combined resting-state functional and structural MR imaging study. Radiology 281:185–192
Tessitore A, Esposito F, Vitale C, Santangelo G, Amboni M, Russo A, Corbo D, Cirillo G, Barone P, Tedeschi G (2012) Default-mode network connectivity in cognitively unimpaired patients with Parkinson disease. Neurology 79:2226–2232
Tozzi V, Balestra P, Bellagamba R, Corpolongo A, Salvatori MF, Visco-Comandini U, Vlassi C, Giulianelli M, Galgani S, Antinori A, Narciso P (2007) Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors. J Acquir Immune Defic Syndr 45:174–182
Vincent JL, Patel GH, Fox MD, Snyder AZ, Baker JT, Van Essen DC, Zempel JM, Snyder LH, Corbetta M, Raichle ME (2007) Intrinsic functional architecture in the anaesthetized monkey brain. Nature 447:83–86
Williams K, Lackner A, Mallard J (2016) Non-human primate models of SIV infection and CNS neuropathology. Curr Opin Virol 19:92–98
Yan CG, Wang XD, Zuo XN, Zang YF (2016) DPABI: data processing & analysis for (resting-state) brain imaging. Neuroinformatics 14:339–351
Zang YF, He Y, Zhu CZ, Cao QJ, Sui MQ, Liang M, Tian LX, Jiang TZ, Wang YF (2007) Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. Brain Dev 29:83–91
Zhang X, Li C (2013) Quantitative MRI measures in SIV-infected macaque brains. J Clin Cell Immunol Suppl 7
Zhao J, Jing B, Chen F, Liu J, Wang Y, Li H (2017) Altered regional homogeneity of brain spontaneous signals in SIV infected rhesus macaque model. Magn Reson Imaging 37:56–61
Zhuang Y, Qiu X, Wang L, Ma Q, Mapstone M, Luque A, Weber M, Tivarus M, Miller E, Arduino RC, Zhong J, Schifitto G (2017) Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naive HIV-infected individuals. J Neuro-Oncol 23:704–712
Zou QH, Zhu CZ, Yang Y, Zuo XN, Long XY, Cao QJ, Wang YF, Zang YF (2008) An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF. J Neurosci Methods 172:137–141
Zuo XN, Xing XX (2014) Test-retest reliabilities of resting-state FMRI measurements in human brain functional connectomics: a systems neuroscience perspective. Neurosci Biobehav Rev 45:100–118
Acknowledgments
The authors would thank all patients and participants in the research and Prof. Yufeng Zang (Hangzhou Normal University) for many important scientific discussions about the resting-state fMRI.
Funding
The work was financially supported by the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support [grant number ZYLX201511] and the National Nature Science of Foundation of China [grant number 81771806]. Bin Jing was financially supported by the Beijing Natural Science Foundation [number 7174282].
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The experiment was conducted according to the guide of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of the Institute of Laboratory Animal Science, CAMS & PUMC.
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Zhao, J., Chen, F., Ren, M. et al. Low-frequency fluctuation characteristics in rhesus macaques with SIV infection: a resting-state fMRI study. J. Neurovirol. 25, 141–149 (2019). https://doi.org/10.1007/s13365-018-0694-5
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DOI: https://doi.org/10.1007/s13365-018-0694-5