Abstract
Rationale: We provide an in-depth description of a comprehensive clinical, immunological, and neuroimaging study that includes a full image processing pipeline. This approach, although implemented in HIV infected individuals, can be used in the general population to assess cerebrovascular health.Aims: In this longitudinal study, we seek to determine the effects of neuroinflammation due to HIV-1 infection on the pathomechanisms of cerebral small vessel disease (CSVD). The study focuses on the interaction of activated platelets, pro-inflammatory monocytes and endothelial cells and their impact on the neurovascular unit. The effects on the neurovascular unit are evaluated by a novel combination of imaging biomarkers.Sample Size: We will enroll 110 HIV-infected individuals on stable combination anti-retroviral therapy for at least three months and an equal number of age-matched controls. We anticipate a drop-out rate of 20%.Methods and Design: Subjects are followed for three years and evaluated by flow cytometric analysis of whole blood (to measure platelet activation, platelet monocyte complexes, and markers of monocyte activation), neuropsychological testing, and brain MRI at the baseline, 18- and 36-month time points. MRI imaging follows the recommended clinical small vessel imaging standards and adds several advanced sequences to obtain quantitative assessments of brain tissues including white matter microstructure, tissue susceptibility, and blood perfusion.Discussion: The study provides further understanding of the underlying mechanisms of CSVD in chronic inflammatory disorders such as HIV infection. The longitudinal study design and comprehensive approach allows the investigation of quantitative changes in imaging metrics and their impact on cognitive performance.
Highlights
Cerebral small vessel disease (CSVD) is a common neurodegenerative disease associated with aging and other neurological diseases that is diagnosed by brain imaging
From the results of this study, we selected two brain areas that provide reliable and reproducible diffusion tensor imaging (DTI) measurements, namely the body and splenium of the corpus callosum (BCC and SCC), we identified other white matter structures that show even more significant differences between human immunodeficiency virus (HIV)- controls and HIV+ subjects
CSVD is associated with an increased likelihood of HIV-associated neurocognitive disorder (HAND) [10], though there is some evidence that the contribution of CSVD to cognitive impairment is independent of that of HIV infection itself [127]
Summary
Cerebral small vessel disease (CSVD) is a common neurodegenerative disease associated with aging and other neurological diseases that is diagnosed by brain imaging. CSVD affects small penetrating arteries, arterioles, capillaries, and venules [1] and is clinically diagnosed by presence of brain atrophy, white matter hyperintensities (WMHs), enlarged perivascular spaces, cerebral microbleeds, and lacunar infarcts. These are detected by T1-weighted (T1w), fluid attenuated inversion recovery (FLAIR), T2-weighted (T2w), T2*-weighted (T2*), and diffusion MRI (dMRI) [2]. Additional neuroimaging techniques to study CSVD in more detail have been proposed and include [3] cutting-edge research sequences that can be used to assess altered microcirculation and blood brain barrier (BBB) dysfunction indirectly by measuring cerebrovascular reactivity (CVR), cerebral blood flow (CBF), white matter microstructure, and tissue susceptibility [4]. CSVD has been associated with markers secreted by myeloid cells [11, 12]
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