White matter microstructure among perinatally HIV-infected youth: a diffusion tensor imaging study

We evaluated white matter microstructure integrity in perinatally HIV-infected (PHIV) youths receiving cART compared to age- and gender-matched healthy youths through DTI metrics using voxel-based morphometry (VBM). We investigated 14 perinatally HIV-infected patients (age 17.9 ± 2.5 years) on cART and 17 healthy youths (HC) (age 18.0 ± 3.0 years) using a 3T MRI scanner. Four DTI-derived metrics were fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Statistical analysis was done with voxel-based analysis of covariance (ANCOVA), with age and gender as covariates. Region-of-interest secondary analyses in statistically significant regions were also performed. Regional increases in FA in the PHIV youths were found in left middle frontal gyrus, right precuneus, right lingual gyrus, and left supramarginal gyrus. Increased MD was found in the right precentral gyrus while decreased MD was found in the white matter of the right superior parietal lobule and right inferior temporal gyrus/fusiform gyrus. Regions of increased/decreased RD overlapped with regions of increased/decreased MD. Both increased and decreased AD were found in three to four regions respectively. The regional FA, MD, RD, and AD values were consistent with the voxel-based analysis findings. The findings are mostly consistent with previous literature, but increased FA has not been previously reported for perinatally HIV-infected youths. Potentially early and prolonged therapy in our population may have contributed to this new finding. Both toxicity of antiretroviral therapy and indolent infection must be considered as causative factors in the DTI metric changes that we have observed.

[1]  Chris Rorden,et al.  Improving Lesion-Symptom Mapping , 2007, Journal of Cognitive Neuroscience.

[2]  J. Church,et al.  Regional brain gray and white matter changes in perinatally HIV-infected adolescents☆ , 2013, NeuroImage: Clinical.

[3]  Jun Yoshino,et al.  Demyelination increases radial diffusivity in corpus callosum of mouse brain , 2005, NeuroImage.

[4]  Frederik Barkhof,et al.  Regional DTI differences in multiple sclerosis patients , 2009, NeuroImage.

[5]  Diffusion tensor imaging in HIV infection: what is it telling us? , 2001, AJNR. American journal of neuroradiology.

[6]  R. Edelman,et al.  Diffusion alterations in corpus callosum of patients with HIV. , 2006, AJNR. American journal of neuroradiology.

[7]  E. Ringelstein,et al.  Early microstructural white matter changes in patients with HIV: A diffusion tensor imaging study , 2012, BMC Neurology.

[8]  Richard Watts,et al.  Diffusion-tensor MR imaging in children with developmental delay: preliminary findings. , 2003, Radiology.

[9]  C. Beaulieu,et al.  The basis of anisotropic water diffusion in the nervous system – a technical review , 2002, NMR in biomedicine.

[10]  Dinggang Shen,et al.  White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients , 2009, NeuroImage.

[11]  Adolf Pfefferbaum,et al.  Diffusion tensor imaging with quantitative fibre tracking in HIV infection and alcoholism comorbidity: synergistic white matter damage. , 2006, Brain : a journal of neurology.

[12]  Systematic review of neuroimaging studies in vertically transmitted HIV positive children and adolescents , 2014, Metabolic Brain Disease.

[13]  Michael Watters,et al.  Greater Than Age-Related Changes in Brain Diffusion of HIV Patients After 1 Year , 2008, Journal of Neuroimmune Pharmacology.

[14]  R. Ellis,et al.  HIV Infection and the Central Nervous System: A Primer , 2009, Neuropsychology Review.

[15]  M. Boivin,et al.  Neurodevelopment in perinatally HIV-infected children: a concern for adolescence , 2013, Journal of the International AIDS Society.

[16]  Martha J. Holmes,et al.  White Matter Abnormalities in Children with HIV Infection and Exposure , 2017, Front. Neuroanat..

[17]  P. Reiss,et al.  Poorer cognitive performance in perinatally HIV-infected children versus healthy socioeconomically matched controls. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  I. Grant,et al.  Cognitive Neuropsychology of HIV-Associated Neurocognitive Disorders , 2009, Neuropsychology Review.

[19]  K. Lim,et al.  Advances in white matter imaging: A review of in vivo magnetic resonance methodologies and their applicability to the study of development and aging , 2006, Neuroscience & Biobehavioral Reviews.

[20]  Ann S. Choe,et al.  Validation of diffusion tensor MRI in the central nervous system using light microscopy: quantitative comparison of fiber properties , 2012, NMR in biomedicine.

[21]  T. Ernst,et al.  A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age , 2004, NeuroImage.

[22]  D. Kolson Neurologic Complications in Persons With HIV Infection in the Era of Antiretroviral Therapy. , 2017, Topics in antiviral medicine.

[23]  G. Noel,et al.  Neuroimaging findings in children perinatally infected with the human immunodeficiency virus. , 1998, The Pediatric infectious disease journal.

[24]  P. Basser,et al.  Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. 1996. , 1996, Journal of magnetic resonance.

[25]  Karl J. Friston,et al.  Voxel-Based Morphometry—The Methods , 2000, NeuroImage.

[26]  K. Robertson,et al.  Antiretroviral neurotoxicity , 2012, Journal of NeuroVirology.

[27]  D. Clifford,et al.  Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance , 2009, AIDS.

[28]  Dan J Stein,et al.  Clinical associations of white matter damage in cART-treated HIV-positive children in South Africa , 2015, Journal of NeuroVirology.

[29]  Dianne Langford,et al.  HIV and antiretroviral therapy in the brain: neuronal injury and repair , 2008, Nature Reviews Neuroscience.

[30]  Xiaoping Hu,et al.  Utility of axial and radial diffusivity from diffusion tensor MRI as markers of neurodegeneration in amyotrophic lateral sclerosis , 2010, Brain Research.

[31]  D. Havlir,et al.  Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort , 2010, Neurology.

[32]  Ursula Bellugi,et al.  More Is Not Always Better: Increased Fractional Anisotropy of Superior Longitudinal Fasciculus Associated with Poor Visuospatial Abilities in Williams Syndrome , 2007, The Journal of Neuroscience.

[33]  P. Reiss,et al.  Cerebral injury in perinatally HIV-infected children compared to matched healthy controls , 2016, Neurology.

[34]  C. Rinaldo,et al.  Proinflammatory cytokines in HIV disease-a review and rationale for new therapeutic approaches. , 2005, AIDS reviews.

[35]  M. Castillo,et al.  Diffusion-tensor MR imaging of the brain in human immunodeficiency virus-positive patients. , 2005, AJNR. American journal of neuroradiology.

[36]  Hangyi Jiang,et al.  DtiStudio: Resource program for diffusion tensor computation and fiber bundle tracking , 2006, Comput. Methods Programs Biomed..

[37]  P. Basser,et al.  Diffusion tensor MR imaging of the human brain. , 1996, Radiology.

[38]  M. Moseley,et al.  HIV-Associated Alterations in Normal-Appearing White Matter: A Voxel-Wise Diffusion Tensor Imaging Study , 2007, Journal of acquired immune deficiency syndromes.

[39]  K. Trinkaus,et al.  Quantification of increased cellularity during inflammatory demyelination. , 2011, Brain : a journal of neurology.

[40]  Lei Wang,et al.  White matter microstructure among youth with perinatally acquired HIV is associated with disease severity , 2015, AIDS.

[41]  J. Fine,et al.  An Updated Systematic Review of Neuroimaging Studies of Children and Adolescents with Perinatally Acquired HIV , 2016 .

[42]  S. Andronikou,et al.  Early Antiretroviral Therapy in HIV-Infected Children Is Associated with Diffuse White Matter Structural Abnormality and Corpus Callosum Sparing , 2016, American Journal of Neuroradiology.

[43]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[44]  R. Edelman,et al.  Monocyte chemoattractant protein-1 correlates with subcortical brain injury in HIV infection , 2006, Neurology.

[45]  John Russell,et al.  Dysmyelination Revealed through MRI as Increased Radial (but Unchanged Axial) Diffusion of Water , 2002, NeuroImage.

[46]  A. Winston,et al.  Differences in the Direction of Change of Cerebral Function Parameters Are Evident over Three Years in HIV-Infected Individuals Electively Commencing Initial cART , 2015, PLoS ONE.

[47]  Xiaoqi Huang,et al.  Increased fractional anisotropy in white matter of the right frontal region in children with attention-deficit/hyperactivity disorder: a diffusion tensor imaging study. , 2010, Neuro endocrinology letters.

[48]  Joong Hee Kim,et al.  Diffusion tensor imaging predicts hyperacute spinal cord injury severity. , 2007, Journal of neurotrauma.

[49]  A. Phulukdaree,et al.  Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women with and without Preeclampsia , 2017, PloS one.

[50]  P. Basser,et al.  Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. , 1996, Journal of magnetic resonance. Series B.

[51]  Patrick W Wright,et al.  The effects of HIV and combination antiretroviral therapy on white matter integrity , 2012, AIDS.

[52]  A diffusion tensor imaging and neurocognitive study of HIV-positive children who are HAART-naïve “slow progressors” , 2012, Journal of NeuroVirology.

[53]  T. Nir,et al.  Brain Imaging and Neurodevelopment in HIV-uninfected Thai Children Born to HIV-infected Mothers , 2015, The Pediatric infectious disease journal.

[54]  John D Seeger,et al.  Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[55]  P. Thompson,et al.  Diffusion imaging, white matter, and psychopathology. , 2011, Annual review of clinical psychology.

[56]  K. Robertson,et al.  HIV, Antiretroviral Therapies, and the Brain , 2010, Current HIV/AIDS reports.

[57]  N. Whitehead,et al.  The neurodevelopment of HIV-infected infants on HAART compared to HIV-exposed but uninfected infants , 2014, AIDS care.

[58]  Dan J Stein,et al.  Evidence for fractional anisotropy and mean diffusivity white matter abnormalities in the internal capsule and cingulum in patients with obsessive-compulsive disorder. , 2012, Journal of psychiatry & neuroscience : JPN.

[59]  P. V. van Zijl,et al.  Three‐dimensional tracking of axonal projections in the brain by magnetic resonance imaging , 1999, Annals of neurology.

[60]  S. Andronikou,et al.  White Matter Signal Abnormalities in Children With Suspected HIV-related Neurologic Disease on Early Combination Antiretroviral Therapy , 2014, The Pediatric infectious disease journal.

[61]  Glyn Johnson,et al.  White matter abnormalities in HIV-1 infection: A diffusion tensor imaging study , 2001, Psychiatry Research: Neuroimaging.

[62]  R. Chaisson,et al.  Natural history of HIV infection in the era of combination antiretroviral therapy. , 1999, AIDS.

[63]  Neuropsychological Function and Cerebral Metabolites in HIV-infected Youth , 2012, Journal of Neuroimmune Pharmacology.

[64]  M. Hughes,et al.  Quality of Life for Children and Adolescents: Impact of HIV Infection and Antiretroviral Treatment , 2006, Pediatrics.

[65]  Dan J Stein,et al.  White-Matter damage in Clade C HIV-positive subjects: a diffusion tensor imaging study. , 2011, The Journal of neuropsychiatry and clinical neurosciences.

[66]  P. Simmonds,et al.  Influence of HAART on HIV-related CNS disease and neuroinflammation. , 2005, Journal of neuropathology and experimental neurology.