Project Summary/Abstract The primary goals of the parent project, Multimodal Imaging of NeuroHIV Dynamics (MIND), are to advance understanding of the etiology of mild to moderate forms of HIV-related cognitive dysfunction by clarifying the role played by altered neuronal circuits, dynamics, and networks using novel neurophysiological and neuro- imaging techniques. The project implements a large-scale multimodal neuroimaging approach that couples the latest breakthroughs in advanced instrumentation and data analyses to identify the pathophysiology of neuroHIV in virally-suppressed adults. Specifically, the approach includes magnetoencephalographic (MEG) imaging to quantify the region- and circuit-level neural dynamics serving cognitive processing, 3-Tesla MRI and multi- modal parcellation methods to map areal brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to quantify GABA levels in multi-voxel slabs of interest identified by the functional modalities. The investigative team includes a unique combination of experts in MEG, MRI/fMRI, MRSI, and cognitive psychology from the University of Nebraska and University of Pittsburgh Medical Centers, and follows the Research Domain Criteria (RDoC) framework to define cognitive constructs. The project’s overarching hypothesis is that HIV-infected adults will exhibit aberrations in local inhibitory circuits, and that these deficits will alter gamma oscillations and thereby impair neuronal coding and interregional functional connectivity in the theta range. With this administrative supplement, we will extend the MIND project to biomarker-positive patients on the Alzheimer’s spectrum (i.e., patients with mild cognitive impairment or mild/moderate Alzheimer’s disease) and add beta-amyloid PET imaging to the overall protocol. With these data, we will determine whether cognitive domain-specific alterations in the neural dynamics differ between patients with HIV-related cognitive impairments and amyloid-positive Alzheimer’s spectrum impairments. Specifically, we will examine the oscillatory dynamics within neural populations serving attention and visual perception (Aim 1), cognitive control (Aim 2), and working memory processing (Aim 3), with the hypothesis that altered neural oscillations will predict impaired behavioral performance and differ between Alzheimer’s spectrum and impaired HIV-infected patients. Finally, we will identify the role of local GABA dysfunction in Alzheimer’s spectrum and HIV-infected patients (Aim 4) and determine whether the regional deposition of beta-amyloid covaries with local GABA concentrations in affected neural populations, suggesting a specific role for GABAergic inhibitory circuits. Importantly, this supplement will allow for direct comparisons between patients with HIV and AD-related cognitive deficits, which is an area of growing concern in the field of neuroHIV due to the potential comorbidity of the two disorders (i.e., HIV-infected patients with AD), particularly since modern antiretroviral therapies have extended the lifespan of HIV-infected adults to that of the general population.

Project Narrative The Multimodal Imaging of NeuroHIV Dynamics (MIND) study uses advanced dynamic functional brain mapping methods, along with the latest in structural, functional, and spectroscopic MRI to evaluate brain circuity and cognitive dysfunction in a large sample of cognitively-impaired and unimpaired HIV-infected adults. Through this administrative supplement, we will add a group of biomarker-positive Alzheimer’s spectrum patients to the overall sample and conduct the same advanced neuroimaging protocol implemented in the MIND study, plus beta-amyloid PET imaging. A key goal is to identify alterations in the neural dynamics that predict the behavioral performance deficits observed in Alzheimer’s spectrum patients, and to determine how these altered dynamics differ from those observed in cognitively-impaired HIV-infected adults.