Blood Brain Barrier Dysfunction in Chronic Alcohol Use Disorder

About This Grant

PROJECT SUMMARY/ABSTRACT Chronic alcohol use disorder (AUD) is associated with neurostructural damage and a pervasive pattern of cognitive deficits, which persist even in detoxified individuals. It has been hypothesized that deterioration of the blood brain barrier (BBB) provides a primary causative mechanism through which repeated high dose exposure to alcohol leads to neuroinflammation, neuronal death and cognitive impairments in chronic AUD. To date, evidence for a role of BBB alterations in the long-term consequences of chronic AUD comes largely from preclinical studies. Although some human post-mortem data support the idea of BBB dysfunction in AUD these data are limited and basic questions about the magnitude and spatial extent of BBB dysfunction, its antecedents, developmental course and its consequences remain unaddressed. A recently developed MRI technique using motion corrected diffusion weighted pseudo-continuous arterial spin labelling (MCDW-pCASL) sequence provides the ability to noninvasively measure water permeability across the BBB and quantify water exchange rate (Kw) in vivo. Critically, this approach is sensitive to more subtle changes in the BBB, whereas earlier methods could only assess the permeability of large molecules. Moreover, because the approach is noninvasive and does not involve injection of contrast agents, it can be implemented in longitudinal and larger scale studies. We propose to develop a research program utilizing this technique to map Kw alterations and determine their correlates in chronic AUD. In an initial pilot-feasibility step of this research program, we propose to scan 30 recently detoxified individuals with a history of severe chronic AUD and 30 age and sex matched controls with the MCDW-pCASL sequence. We will test the hypothesis that chronic AUD is associated with reduced BBB integrity as reflected in altered Kw and will determine how regionally diffuse or specific these alterations are. We will also collect data on drinking history (age of first heavy drinking, total alcohol consumed over lifetime, frequency of binge drinking) to determine the extent to which this history predicts the magnitude of alterations in the BBB. We will also collect high-resolution structural MRI measures of grey matter volume/cortical thickness and diffusion tensor imaging of white matter microstructure, as well as measures of cognitive functioning and premorbid IQ to test hypotheses that the magnitude of BBB alterations predict the neural and cognitive deficits associated with chronic AUD. If successful, these studies will support the development of large-scale studies to understand the evolution and impact of BBB alterations in AUD. This line of work could have significant clinical implications given the recent development of techniques for targeting BBB structure and function. Indeed, if the MCDW-pCASL sequence proves sensitive to BBB dysfunction in AUD, it could potentially be used as a precision medicine technique to identify those individuals who might benefit from BBB interventions and to directly monitor the impact of those treatments in vivo.