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Redistribution of brain glucose metabolism in people with HIV after antiretroviral therapy initiation
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July 1 2021, AIDS, Zeping Wanga, Maura M. Manionb, Elizabeth Laidlawb, Adam Rupertc, Chuen-Yen Laud, Bryan R. Smithe, Avindra Nathe, Irini Seretib and Dima A. Hammouda
aCenter for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health,
bLaboratory of Immunoregulation, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, cLeidos Biomedical Research Inc., Frederick National Laboratory
This was a prospective observational study of 22 PWH. The PWH participants had CD4+ T-cell counts of less than 100 cells/μl at baseline, were naive to ART and were willing to start therapy.
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In summary, our findings suggest that there is differential regional susceptibility of the brain to HIV infection with maximal effects in the basal ganglia, particularly the putamen, and the thalamus. ART has a significant role in tempering neuroinflammatory changes in the brain in concert with the abatement of systemic viral replication and inflammation. Long-term subcortical decreases in glucose metabolism, on the other hand, are likely the result of irreversible neuronal damage associated with pretreatment neuroinflammatory changes, although other factors, including ART toxicity [52,53] and cardiovascular disease [16], cannot be ruled out. Our findings support the importance of early initiation of treatment and controlling viral replication/neuroinflammation in minimizing neurological damage, and suggest that FDG PET may be a sensitive technique for monitoring the effects of ART in this population.
We also evaluated a subset of patients who were imaged after approximately two years of uninterrupted ART and found evidence for differential long-term injury in various brain regions: subcortical hypometabolism further progressed in the basal ganglia and thalamus, suggesting an element of irreversible injury and neuronal loss [13,33-35], while cortical metabolism did not change appreciably. With the limitations of a small sample number, our findings could reflect higher susceptibility of the thalamus and subcortical regions to the effects of the virus compared to the more resilient cortical structures. These findings are in concordance with multiple prior MR volumetric studies repeatedly demonstrating volume loss in subcortical structures [12,13,18]. In one of those studies, striatal volume loss was noted despite immediate initiation of ART in the acute stage of infection [18].
Introduction
The introduction of combination antiretroviral therapy (cART) has greatly reduced the morbidity and mortality associated with HIV infection [1,2]. Despite these advances, rates of HIV-associated neurocognitive impairment remain high, with asymptomatic and mild neurocognitive impairment still reported to occur in around 30-50% of patients [3-6]. HIV enters the central nervous system (CNS) early in the course of infection [7] via infected monocytes and lymphocytes [3,8-10]. Once in the brain, HIV infection of macrophages, microglial cells and astrocytes leads to chronic inflammation, which is believed to be the primary source of neuronal damage in untreated people living with HIV (PWH) [3,11]. The pathophysiology of CNS disease in PWH after treatment, however, remains less well understood.
Although multiple studies have investigated neurocognition [1,2] and brain volumetric changes in treated PWH [12,13], few studies have focused on the acute and chronic effects of ART initiation from a metabolic perspective. Whether an inflammatory component of the infection is acutely detectable in the brains of infected patients, and how this inflammation is modified by effective ART, remains unclear. In this study, we aimed to better understand brain metabolic changes in a group of late-presenting ART-naive PWH patients with low CD4+ cell counts [14], as it relates to ART initiation and maintenance. To assess glucose metabolism in the cortical and subcortical regions of the brain as a reflection of neuroinflammation and neuronal function, participants underwent 18F-Fluorodeoxyglucose (FDG) PET/CT scans before and once (n = 22) or twice (n = 11) after initiation of ART (short and long-term follow-up). FDG uptake values from the baseline and long-term treated PWH scans were also compared with values obtained from a group of uninfected HIV-negative controls. Finally, we looked for associations between FDG uptake in PWH and biomarkers of disease activity and immune activation in the periphery, in an attempt to correlate changes in metabolic activity with overall disease progression.
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Abstract
Objective:
We evaluated brain glucose metabolism in people living with HIV (PWH) with [18F]-Fluoro-Deoxyglucose (FDG) PET/computed tomography (CT) before and after antiretroviral therapy (ART) initiation.
Design:
We conducted a longitudinal study wherein ART-naive late-presenting untreated PWH with CD4+ cell counts less than 100 cells/μl were prospectively assessed for FDG uptake at baseline and at 4-8 weeks (n = 22) and 19-26 months (n = 11) following ART initiation.
Methods:
Relative uptake in the subcortical regions (caudate, putamen and thalamus) and cortical regions (frontal, parietal, temporal and occipital cortices) were compared across time and correlated with biomarkers of disease activity and inflammation, in addition to being compared with a group of uninfected individuals (n = 10).
Results:
Before treatment initiation, putaminal and caudate relative FDG uptake values in PWH were significantly higher than in uninfected controls. Relative putaminal and thalamic uptake significantly decreased shortly following ART initiation, while frontal cortex values significantly increased. FDG uptake changes correlated with changes in CD4+ cell counts and viral load, and, in the thalamus, with IL-6R and sCD14. Approximately 2 years following ART initiation, there was further decrease in subcortical relative uptake values, reaching levels below those of uninfected controls.
Conclusion:
Our findings support pretreatment basal ganglia and thalamic neuroinflammatory changes in PWH, which decrease after treatment with eventual unmasking of long-term irreversible neuronal damage. Meanwhile, increased frontal cortex metabolism following ART initiation suggests reversible cortical dysfunction which improves with virologic control and increased CD4+ cell counts. Early initiation of treatment after HIV diagnosis and secondary control of inflammation are thus necessary to halt neurological damage in PWH.
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