Age exacerbates HIV-associated white matter abnormalities

Abstract

Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV-) individuals aged 23–79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV- participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.

White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration

“…We detected no age and HIV status interaction on the DTI parameters. This is similar to the Dutch-British study (Su et al 2016) but different from a recent American study (Seider et al 2015). The American study included a much wider range of ages (23-79), but only 68% were undetectable; while both our study and the European study focused on undetectable middle-aged HIV+ persons (mean age 55 and 53, respectively).…”

“…resulted in inconsistent results. Moreover, variations in the studied HIV+ participants in relation to their combination antiretroviral (cART) status, level of viral suppression, the nature of HIV disease , and their demographics (mainly age) (Towgood et al 2012;Chang et al 2008;Gongvatana et al 2011;Seider et al 2015) have probably contributed to a lack of consistency. Altogether, while DTI may be useful at characterizing the extent of WM injury in cases with moderate to severe HIV-associated neurocognitive disorder (HAND) (Chang et al 2008;Chen et al 2009;Gongvatana et al 2011) or advanced untreated HIV infection (Hoare et al 2011;Leite et al 2013;Pfefferbaum et al 2009) (when HIV replication is the cause of the WM damage), its use at elucidating what may be the HIV-related neuropathology substrate in virally suppressed HIV infection is less clear.…”

HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment

“…Likewise, changes in bioenergetics, as measured with neuroimaging 70–72 and metabolomic appraches 73,74 , are readily apparent in individuals with ANI or MND compared with cognitively normal HIV+ individuals, as are accumulations of bioactive lipids, such as ceramide, and sterol markers of cell stress 75,76 . Brain structural changes 84 and progressive impairments in energy and lipid metabolism 75,77–80 , immune regulation 67,81,82 and metabolism 74,83 worsen with age and duration of infection 50,85–89 . Whether markers of neuronal and axonal injury are elevated during acute infection is not entirely clear.…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Despite successful cART/HAART treatment in HIV-positive patients, they continue to have persistent untraceable viral load in the CNS, resulting in WM abnormalities and neuro-inflammation, and thus leading to mild to severe cognitive impairment and brain atrophy at older ages [240, 241]. Multiple studies show a significant interaction between age and HIV infection, as HIV-infected patients frequently exhibit a greater extent of structural deformation in cognitive regions of the brain with aging, including abnormalities in whole-brain WM hyperintensities and fronto-subcortical WM integrity, compared with age-matched HIV-negative individuals [242–245]. Diffusion tensor imaging (DTI) revealed the marked degeneration of WM microstructures, expressed as large differences between fractional anisotropy and mean diffusivity, that is highest in the corpus callosum and projection fibers of the corona radiata in HIV-positive elderly patients compared with age-matched controls, which is consistent with earlier studies suggesting that WM-associated microstructural alterations lead to severe dementia and motor dysfunction [246, 247].…”

“…On the other hand, HIV-negative and early HIV-infected (≤1 year of viral exposure) patients exhibit only disruption of the BBB and no significant alterations in WM integrity [248]. Moreover, aging HIV-infected patients exhibit greater WM hyper-intensities and lower fractional anisotropy in the anterior corona radiata due to hepatitis C virus coinfection, the more likely development of AIDS, and higher CD4-positive cell counts as a marker of hyper-activation of inflammatory responses [245, 249]. …”