Project Summary/Abstract Mild cognitive impairment (MCI) remains a critical problem in patients infected with HIV, but it is also commonly seen in patients with diabetes, early Alzheimer’s disease (AD), Parkinson’s disease, and many other conditions, and in its mildest form is also a feature of healthy aging. Over six million Americans are currently living with AD spectrum conditions (i.e., AD/MCI) and roughly half of patients infected with HIV are cognitively impaired, not to mention the vast numbers with other etiologies. Thus, there is a clear and immediate need to understand the neurophysiological basis of these impairments and, in the context of HIV, these needs are central to PAR-24-091, which calls for innovative approaches to identify how HIV specifically primes the system for cognitive decline. While the mechanisms that underlie cognitive impairment are poorly understood, many studies have probed the systems-level brain circuits that appear to play a prominent role. These studies have been largely successful in identifying the circuits, yet we still have a limited understanding of the physiology and dynamics within these networks, and the level of specificity to HIV related neuropathology versus cognitive impairment more generally. Quantifying the neural dynamics in affected circuits is critical, as different oscillatory responses (e.g., theta, alpha, gamma activity) have been found to code for distinct cognitive faculties, even when they occur in overlapping regions of the brain. Further, current approaches have generally not probed the dynamics, and have not had the sensitivity or specificity to reliability distinguish HIV-related pathology from similar conditions and/or healthy aging. Thus, new tools and approaches are needed. Herein, we use an emerging dynamic functional mapping method based on next-generation magnetoencephalography (MEG) to quantify oscillatory responses serving cognitive task performance and spontaneous neural activity during rest in three demographically matched groups (i.e., cognitively impaired adults with HIV, patients on the AD spectrum, and cognitively normal healthy aging adults). Our novel dynamic mapping approach uses the latest in MEG instrumentation to provide spectrally resolved maps with excellent temporal and spatial precision, which we will integrate with high-resolution structural maps of areal brain architecture based on multimodal parcellation, maps of amyloid PET deposition, and a battery of domain-specific cognitive assessments. Specifically, we will identify the oscillatory dynamics serving visual attention and visuo-spatial processing (Aim 1), as well as neural entrainment (Aim 2), and quantify spontaneous cortical activity at rest (Aim 3). Our overarching hypotheses are that these dynamic neurophysiological maps will delineate unique pathological features underlying HIV-related cognitive decline relative to that observed in AD spectrum conditions and healthy aging and predict domain-specific cognitive dysfunction. Importantly, our team has extensive experience working with these patient populations and developing circuit-level markers of brain pathology using advanced multimodal neuroimaging.

Project Narrative Mild cognitive impairment is a defining feature of early Alzheimer’s disease, but it is also associated with many other conditions such as HIV-infection, where the prevalence rate is much higher than the general population. Despite this, there is a fundamental lack of scientific knowledge regarding the shared and distinct mechanisms underlying cognitive impairment in people with HIV, early Alzheimer’s disease, and normal aging adults. The current project uses a state-of-the-art dynamic functional mapping approach to identify the specific brain circuits and neural processes that uniquely contribute to cognitive impairment in these different populations.