Novel Neuroimaging Assessments of Glymphatic Disruption in Humans, a Plausible Key Pathophysiological Mechanism for CNS Lupus
Abstract
Lupus can attack multiple organs of the body because the immune system, which is normally protective, acts against body tissues systemwide. Disruption of blood vessels, essential for maintaining all tissues, may be one common route by which lupus causes tissue degeneration. Commonly, lupus can involve the brain resulting in some of the greatest loss of quality of life, including cognitive decline. Development of imaging or biological markers that reliably relate to symptoms of lupus in the brain has been elusive. In the brain, there is a special relationship between neurons and other, supporting, cells, and the vasculature such that blood vessels form a blood-brain barrier to tightly regulate the exchange of nutrients and immune-related components between the blood and gray matter or white matter tissue. The vasculature in the brain is also highly responsive to the energy needs of the neurons by changing blood flow to deliver more oxygen regionally when neurons become more active. This physiological relationship is described as the neurovascular unit. Neuron degeneration due to lupus is being investigated, in part, as possibly resulting from breakdown of the blood-brain barrier, allowing immune-reactive components of the blood to reach neurons, or from loss of responsiveness of blood vessels to energy needs of neurons. This can result in cognitive dysfunction and to loss of brain tissue volume. This project introduces another component of the neurovascular unit that may add a new dimension to the characterization of how lupus causes neuronal degeneration. The so-called glymphatic system has recently been described in rodents. Cerebrospinal fluid, which fills the spaces surrounding the brain, is transported along channels that surround the brain s arteries as they penetrate deep into brain tissue. The fluid is then driven out of the channels, through the tissue, to be collected in similar channels that surround veins. Through these channels, fluid is transported back to the brain surface. It is thought that this glymphatic circuit is important for circulation of immune cells and for clearance of waste from the tissue. With poor glymphatic function, toxic substances may accumulate or regulation of immune cell exchange may be impaired. Lupus may cause disruption of the glymphatics by clogging the channel flow via inflammation. The flow through the channels is also thought to be driven by natural pulsation of the associated blood vessels due to respiration or the cardiac cycle. Degradation of vascular integrity by lupus may also impact this vessel responsiveness to impair glymphatic flow. We aim to develop novel magnetic resonance imaging tools to characterize structural and functional integrity of the glymphatic system and to apply those tools to demonstrate that lupus alters the glymphatic system. The imaging tools will attempt to (1) detect flow of fluid from the brain surface into tissue, (2) determine the structural integrity of the glymphatic channels, and (3) ascertain response of brain blood vessels to the respiratory cycle. Each tool will be applied to compare, regionally, each glymphatic feature between a group of lupus patients and healthy controls. This work will address several focus areas of the Lupus Research Program. It explores a new pathophysiological mechanism for lupus in the brain using new imaging tools. Findings of imaging signatures of glymphatic breakdown could form new avenues for the accurate diagnosis, staging, and treatment of lupus when it impacts the brain. The imaging tools may well be adapted for routine radiological workups of lupus patients, including children, even well before overt signs of cognitive deficit. Application to the clinic on a developmental basis could be achieved within a year. Applicability to individual patients (for making patient- specific diagnoses or staging) would take several years of development and accumulation of data to allow the use of advanced algorithms. Our g
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810615
Entities
People
- Mark DiFrancesco
Organizations
- United States Army