Independent and Combined Effects of Chronic HIV-Infection and Tobacco Smoking on Brain Microstructure

Abstract

HIV-infected individuals (HIV+) have 2-3 times higher prevalence of tobacco smoking than the general U.S. population. This study aims to evaluate the independent and combined effects of tobacco-smoking and HIV-infection on brain microstructure and cognition using a 2 × 2 design. 21 HIV + Smokers, 25 HIV + Nonsmokers, 25 Seronegative (SN)-Smokers and 23 SN-Nonsmokers were evaluated using diffusion tensor imaging. Fractional anisotropy (FA), mean (MD), radial (RD) and axial (AD) diffusivity were assessed in 8 major cerebral fiber tracts and 5 subcortical regions. Cognitive performance in 7 neurocognitive domains was also assessed. Compared to SN, HIV+ had higher AD in genu of corpus callosum (GCC, p = 0.002). Smokers also had higher diffusivities in GCC, splenium of corpus callosum (SCC), anterior corona radiata (ACR), sagittal stratum (SS) and superior fronto-occipital fasciculus (SFO), than Nonsmokers (p-values<0.001-0.003). Tobacco-Smoking and HIV-infection showed synergistic effects on AD_SS (p = 0.002) and RD_SFO (p = 0.02), but opposite effects in FA_putamen (p = 0.024). Additive effects from HIV+ and Tobacco-Smoking were observed in 9 other white matter tracts, with highest diffusivities and lowest FA in HIV + Smokers. Higher diffusivities in the GCC, SCC, ACR and SS predicted poorer cognitive performance across all participants (p ≤ 0.001). Higher AD_GCC also predicted slower Speed of information processing and poorer Fluency and Attention only in HIV + Smokers (p = 0.001-0.003). Chronic tobacco smoking and HIV-infection appear to have additive and synergistic adverse effects on brain diffusivities, suggesting greater neuroinflammation, which may contribute to poorer cognition. Therefore, chronic tobacco-smoking may be a risk factor for HIV-associated neurocognitive disorders. Graphical Abstract ᅟ.

Keywords: Diffusion tensor imaging; HIV; Microstructure; Tobacco use.

Fig. 1

a The white matter regions of interest with HIV main effects (left to right) are shown: SCC = Splenium of the Corpus Callosum, CGC = Cingulum Cingulate Gyrus, SFO = Superior Fronto-Occipital Fasisculus, GCC = Genu of Corpus Callosum, ALIC = Anterior Limb of Internal Capsule. b HIV+ participants had higher axial diffusivities than SN participants in these white matter regions (GCC, SCC, CGC, ALIC, and SFO). c Radial diffusivity in the CGC was higher in HIV+ than SN control participants, with or without tobacco smoking. d Mean diffusivity in four regions (GCC, SCC, CGC, ALIC) was higher in HIV+ than controls. Only AD in GCC remained significant after Holm correction. SN=Seronegative Nonsmokers, SN_S = Seronegative_Smokers, HIV = HIV + Nonsmokers, HIV + S=HIV + Smokers

Fig. 2

a White matter brain regions that show Tobacco-Smoking effects or Smoking-by-HIV Interaction Effects are shown (left to right): SS=Sagittal Striatum, SCC=Splenium of the Corpus Callosum, CGC=Cingulum Cingulate Gyrus, SFO=Superior Fronto-Occipital Fasisculus, BCC=Body of Corpus Callosum, GCC = Genu of Corpus Callosum, ACR = Anterior Corona Radiata, Put = Putamen. b & c Bargraphs showing Smokers typically had lower FA and higher axial diffusivity (AD) than nonsmokers in these white matter regions. d & e Smokers also had higher radial (RD) and mean diffusivities (MD) across all these brain regions; however, in the SS and SFO, only HIV+ Smokers had higher diffusivities than SN_Smokers, while HIV had similar diffusivities as the SN (interaction effects). f While HIV+ Smokers had higher FA than HIV + Nonsmokers, SN smokers had lower FA than SN- Nonsmokers in the putamen. Asterisks indicate p-values that remained significant after Holm correction for multiple comparisons. SN=Seronegative Nonsmokers, SN_S=Seronegative_Smokers, HIV = HIV+ Nonsmokers, HIV + S=HIV+ Smokers

Fig. 3

Brain regions with abnormal white matter diffusivity predicted performance on the motor function, learning, fluency, attention and speed. a-b Slower Fine Motor Performance is predicted by higher diffusivity in the Genu of the Corpus Callosum (GCC_AD) and Sagittal Striatum (SS_AD). c-d) Poorer Learning is predicted by higher diffusivity in the Anterior Corona Radiata (ACR_AD) and Splenium of the Corpus Callosum (SCC_RD). e-g) Higher axial diffusivity in the Genu of the corpus callosum (GCC_AD) predicted Slower Speed of Information Processing, Fluency and Attention only in the HIV + Smoker group but not in the other groups (group-interaction-p values = 0.001–0.003). SN=Seronegative Nonsmokers, SN_S=Seronegative_ Smokers, HIV = HIV+ Nonsmokers, HIV + S=HIV+ Smokers