Cocaine use disorder (CUD) can cause vascular disease mainly through chronic vasoconstriction effects. Atherosclerosis can be present in the carotid artery (CA) even without overt clinical symptoms. Once symptoms are observable, the artery is usually damaged and cerebral ischemia can ensue, a common fatal outcome in CUD. Indeed, while there are postmortem studies documenting arterial disease in individuals with CUD (iCUD), studies for early in-vivo detection lag behind with catastrophic consequences. Here we will leverage the significant advances made in imaging for early detection of atherosclerosis in asymptomatic populations who are nevertheless at increased risk for vascular disease by MPI Fayad; such early detection is crucial for guiding prevention efforts. Specifically, we will use a hybrid scanner whereby positron emission tomography (PET) with the radiotracer 18F- fluorodeoxyglucose (18F-FDG) quantifies vessel-wall inflammation in atherosclerotic plaques while magnetic resonance imaging (MRI) with a 3-dimensional (3D) dark-blood scan characterizes carotid plaque burden. Such simultaneous state-of-the-art previously validated PET/MRI CA imaging has never before been applied for early atherosclerosis detection in asymptomatic drug addicted individuals. Targeting this population for early detection is of particular urgency now that the “Crack generation” (of the mid 80s) is aging. Following decades of cocaine and comorbid tobacco and alcohol use, these iCUD are at an especially high risk for vascular disease and atherosclerosis. Nevertheless, given factors inherent to drug addiction, relevant diagnoses in this population are only made when it is too late to intervene (hence the preponderance of post-mortem studies). We hypothesize that markers of CA atherosclerosis will be detected in asymptomatic iCUD, as related to their cocaine, tobacco, and alcohol use, at levels comparable, or even surpassing, those detected in individuals with known risk factors for cardiovascular disease but without CUD. The bilateral internal CAs are the primary conduits of oxygenated blood to the cerebral hemispheres and indeed individuals with cardiovascular disease demonstrate cognitive decline (especially of attention, memory and executive function), recently suggested to be modulated by brain network connectivity (especially in brain networks innervated by the internal CAs and subserving salience/control and reward processing) as measured by resting-state functional MRI. Following a series of studies conducted by MPIs Alia-Klein and Goldstein, where similar resting-state inefficiencies were reported in iCUD, modulated by severity of drug use and accompanied by similar cognitive dysfunction, here we postulate that the CA disease markers in iCUD will correlate with neural network connectivity and cognitive function. Beyond the mechanistic inventiveness of this proposal, linking of the carotid to brain function for the first time in drug addiction, it also addresses a public health imperative for early detection of the preclinical markers of atherosclerosis in iCUD. Once pathology is identified, and especially if identified at an early stage, timely intervention can prevent the progression into emergencies, impairments and premature mortality that comprise an enormous cost to society.

PROJECT NARRATIVE Chronic cocaine use (as well as comorbid cigarette smoking and alcohol use) can cause vascular disease. Although the Crack-Cocaine epidemic from the mid-1980s has lessened, with a 3-fold increase in emergency department cocaine-related visits since the end of the 1990s, the vascular consequences of chronic drug use are evident among addicted individuals of that generation. There is a public health imperative to detect early markers of vascular disease, as associated with brain function, to reduce excess morbidity and premature mortality, especially in this aging population.