HIV infected individuals, especially those older, are at increased risk of developing cerebrovascular disease (CBVD). While most of the recent investigations have focused on large vessel disease, cerebral small vessel disease (CSVD) has received much less attention despite its known role and long-term effect on cognitive performance and potentially more direct link to HIV-associated immune dysregulation. CSVD is diagnosed via neuroimaging. Typical findings include small subcortical infarcts, lacunes, white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds and brain atrophy. Quantitative MR techniques assess indirectly the altered microcirculation and blood brain barrier (BBB) by measuring vascular reactivity, cerebral blood flow, white matter microstructure and tissue susceptibility. Importantly, these quantitative imaging modalities can measure even subtle brain abnormalities that escape the evaluation by standard clinical imaging techniques. CSVD has been associated with markers secreted by myeloid cells. This is particularly relevant to HIV infected individuals. We and others have shown that the aberrant platelet activation during HIV/SIV infection causes an increase in platelet-monocyte complexes (PMCs) that drives monocyte maturation from CD14+/CD16- to the pro-inflammatory CD14(low)/CD16+ phenotype and that the reduced numbers of CD14+/CD16- monocytes are associated with pro-AS changes, BBB permeability and aging. Thus, PMCs could serve as markers and a therapeutic target of CSVD. Based on these observations, we hypothesize that PMCs, by affecting vascular permeability and reactivity, play a crucial role in mediating CSVD, especially in older HIV infected individuals. In a well characterize cohort for CBVD risk factors that includes an older-enriched HIV population (age?50) and age matched uninfected individuals, we propose to address the following Specific Aims pertinent to CSVD in a 3-year longitudinal study.
In Aim 1 we will assess whether changes in vascular reactivity (measured via rs-fMRI) and white matter microstructural integrity (measured via DTI) are associated with levels of PMCs. In Sub-Aim 1 we will determine whether areas with increased tissue susceptibility and decreased vascular reactivity are associated with decreased cerebral blood flow (CBF).
In Aim 2 we will determine whether changes vascular reactivity and white matter microstructural integrity are associated with soluble products of pro-inflammatory monocytes (plasma levels of sCD163, neopterin, and HMGB1), platelet activation (platelet factor 4 [PF-4]) and with plasma markers of endothelial dysfunction (intercellular adhesion molecule 1 [sICAM- 1], vascular cellular adhesion molecule-1 [sVCAM-1], osteoprotegerin and lipoprotein-associated phospholipase A2 [Lp-PLA2] mass). In Sub-Aim 2 we will determine whether changes in brain iron deposition are associated with levels of PMCs, PF-4, plasma monocyte and endothelial soluble products.
In Aim 3 we will model data generated from the previous aims in the context of cognitive performance.
Over a million people are thought to be HIV infected in the US and it is projected that by 2015 more than half of all HIV+ individuals will be over the age of 50. However, aging is associated with increased incidence of cardiovascular and cerebrovascular disease. In particular cerebral small vessel disease (CSVD) is of concern because of its frequency and impact on cognitive performance. Interestingly, CSVD has been associated with markers secreted by myeloid cells. This is particularly relevant to HIV infected individuals because immune dysregulation persists even in optimally cART treated individuals. Our proposal is centered on the effect of platelet-monocyte complexes (PMCs) that drives monocyte maturation from CD14+/CD16- to the pro- inflammatory CD14(low)/CD16+ phenotype leading to pro-atherosclerosis vessel wall changes, vessel wall damage and increased blood brain barrier permeability. The information acquired will inform us on preventive strategies for CSVD that can be developed in older HIV infected individuals.