The NVBI has been studying pathologic states that occur at the interface between blood vessels and the brain. This encompasses acute cerebral ischemia caused by an occluded blood vessel as well as chronic cerebral ischemia that can be associated with dementia. To do this we developed an MRI method for evaluating the integrity of the blood-brain barrier (BBB). The BBB is a part of the neurovascular unit which protects the brain from elements in the circulating blood and may also facilitate clearance of elements from the brain itself. Thus dysfunction of the BBB not only opens up the brain to injury but also may affect cerebral homeostasis. Our initial work focused on studying both acute disruption of the BBB in the setting of an ischemic event, as well as, but separate from, chronic disruption of the BBB associated with vascular cognitive impairment. However, through our body of work it has become clear that these two processes are inter-related and more appropriately studied in conjunction with each other. BBB disruption is now treated as an omniphasic continuum. We had previously characterized the role of an acutely disrupted BBB in the risk of hemorrhagic complications in patients treated with thrombolysis (Leigh et al., Stroke, 2014) and thrombectomy (Leigh et al., Neurology, 2016). We further refined our understanding of the BBB in this early stage of ischemia differentiating reversible dysfunction of the BBB from rupture of the BBB that is associated with hemorrhagic complications (Simpkins et al., Stroke, 2016). We are currently characterizing the BBB disruption in a large cohort of patients who were not treated due to a delay in arriving to the hospital with the goal of identifying a population that could be treated in the future based on BBB imaging. More recently we demonstrated BBB disruption in parts of the brain remote from the acute lesion identifying a link to chronic cerebral small vessel disease (Arba et al., Neurology, 2017). We further studied this remote BBB disruption in patients white matter hyperintensities investigating the role of vascular risk factors (Gupta et al., J Stroke Cerebrovasc Dis, 2018). We identified a previously unrecognized link between the severity of acute ischemia and disruption of the blood ocular barrier in stroke patients (Hitomi et al., Neurology, 2018). These results have led us to conclude that the focal ischemic process is having a diffuse effect on the central nervous system. We hypothesize that this diffuse effect plays a role in the development of subsequent vascular cognitive impairment and dementia. It is known that an incident ischemic event can result in a subsequent acceleration of cognitive decline in the years that follow. The mechanism of this relationship is unknown however our preliminary data suggest that BBB disruption plays a key role as a marker for the complex relationship between local and diffuse mediators that result in dysfunction of the neurovascular unit and subsequent cognitive decline. Thus we are studying the chronic effects of acute ischemia prospectively in protocol 18-N-0020 The Natural History of Blood-Brain Barrier Disruption in Stroke Patients with White Matter Hyperintensities (A Cohort Study). This study is currently enrolling and is listed on clinicaltrials.gov with identifier: NCT03366129. https://clinicaltrials.gov/ct2/show/NCT03366129 We also continue to work on developing new MRI tools for studying cerebrovascular disease as described in our review paper: Leigh et al., J Cereb Blood Flow Metab, 2017.
Showing the most recent 10 out of 17 publications
