Pathways from Chronic Methamphetamine Use to Neurological Dysfunction in People with HIV: High-Dimensional Fusion of Systems Biology and Multimodal Neuroimaging - Project Summary/Abstract People with HIV (PWH) remain at an elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, and research targeting these comorbidities is one of four overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Over the past decade, our work has focused on identifying the neurological origins of these impairments and determining the impact of substance use, which has led to the exciting discovery of neurophysiological markers that distinguish cognitively impaired PWH from unimpaired PWH, patients with Alzheimer’s disease or mild cognitive impairment, and healthy aging controls. We now propose to embark on the next stage of this research program through a transformational team science project, which will leverage these markers as primary outcomes in high-dimensional models that include key molecular pathways thought to be aberrant in PWH and methamphetamine use disorder (METH). The molecular precursors and pathways that lead to dysfunction in neural circuits serving cognitive processing in PWH remain poorly understood, and this is a critical barrier to the development of new pharmacotherapeutics. Given the scale and complexity of this barrier, we contend that a team science approach is required to deliver the transformational discoveries that are ultimately needed to significantly advance the field. Thus, we have assembled a multidisciplinary team with expertise in neuroHIV, addiction science, clinical psychology, systems biology, cognitive and computational neuroscience, signal processing, neurophysiology, and machine learning. Our overarching hypotheses are that HIV and chronic methamphetamine use imbalances mitochondrial redox environments, triggering increases in inflammation and elevated subcortical iron levels in key brain structures, which then leads to altered neurotransmitter levels, aberrant oscillations and neurophysiological dynamics, and ultimately, cognitive decline in PWH. To address this, our team science approach will enable the latest tools of systems biology to be integrated with state-of-the-art multimodal neuroimaging using both high-dimensional structural equation modeling and advanced variants of machine learning. We will maximize rigor by using a large, deeply-phenotyped sample of PWH and METH who are demographically matched to three other groups who vary based on HIV and METH status in the context of a longitudinal study. Importantly, if confirmed, treatments aimed at this molecular pathway could have a major impact, as we have repeatedly shown that the end point (i.e., altered brain dynamics) distinguishes cognitively impaired PWH from unimpaired PWH and those with other forms of cognitive dysfunction. In sum, while past studies have provided critical advances on the neural circuitry and dynamics underlying cognitive impairments in PWH who do and do not use illicit substances, the primary mechanisms and pathways leading to such dysfunction have remained beyond reach. Herein, we will use a high- dimensional computational approach to identify the modulatory role of mitochondrial redox environments and inflammation on subcortical brain iron, neurotransmitter levels, neuronal dynamics, and cognitive dysfunction.
