Gadobutrol

In a recent study of the brain's waste drainage system, researchers discovered a direct connection between the brain and its tough protective covering, the dura mater. These links may allow waste fluid to leave the brain while also exposing the brain to immune cells and other signals coming from the dura. This challenges the conventional wisdom which has suggested that the brain is cut off from its surroundings by a series of protective barriers, keeping it safe from dangerous chemicals and toxins lurking in the environment. In a recent study of the brain's waste drainage system, researchers from Washington University in St. Louis, collaborating with investigators at the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institute of Health (NIH), discovered a direct connection between the brain and its tough protective covering, the dura mater. These links may allow waste fluid to leave the brain while also exposing the brain to immune cells and other signals coming from the dura. This challenges the conventional wisdom which has suggested that the brain is cut off from its surroundings by a series of protective barriers, keeping it safe from dangerous chemicals and toxins lurking in the environment. "Waste fluid moves from the brain into the body much like how sewage leaves our homes," said NINDS's Daniel S. Reich, M.D., Ph.D. "In this study, we asked the question of what happens once the 'drain pipes' leave the 'house' -- in this case, the brain -- and connect up with the city sewer system within the body." Reich's group worked jointly with the lab of Jonathan Kipnis, Ph.D., a professor at Washington University in St. Louis. Reich's lab used high-resolution magnetic resonance imaging (MRI) to observe the connection between the brain and body's lymphatic systems in humans. Meanwhile Kipnis's group was independently using live-cell and other microscopic brain imaging techniques to study these systems in mice. Using MRI, the researchers scanned the brains of a group of healthy volunteers who had received injections of gadobutrol, a magnetic dye used to visualize disruptions in the blood brain barrier or other kinds of blood vessel damage. Large veins are known to pass through the arachnoid barrier carrying blood away from the brain, and these were clearly observed on the MRI scans. As the scan progressed, a ring of dye appeared around those large veins that slowly spread out over time, suggesting that fluid could make its way through the space around those large veins where they pass through the arachnoid barrier on their way into the dura. Kipnis's lab was making similar observations in mice. His group injected mice with light-emitting molecules. Like with the MRI experiments, fluid containing these light-emitting molecules was seen to slip through the arachnoid barrier where blood vessels passed through. Together, the labs found a "cuff" of cells that surround blood vessels as they pass through the arachnoid space. These areas, which they called arachnoid cuff exit (ACE) points, appear to act as areas where fluid, molecules, and even some cells can pass from the brain into the dura and vice versa, without allowing complete mixing of the two fluids. In some disorders like Alzheimer's disease, impaired waste clearance can cause disease-causing proteins to build up. Continuing the sewer analogy, Kipnis explained the possible connection to ACE points: "If your sink is clogged, you can remove water from the sink or fix the faucet, but ultimately you need to fix the drain," he said. "In the brain, clogs at ACE points may prevent waste from leaving. If we can find a way to clean these clogs, its possible we can protect the brain." One implication of ACE points is that they are areas where the immune system can be exposed to and react to changes occurring in the brain. When mice in Dr. Kipnis's lab were induced to have a disorder where the immune system attacks the myelin in their brain and spinal cord, immune cells could be seen around ACE points and even between the blood vessel wall and the cuff cells; this led over time to a breakdown of the ACE point itself. When the ability of immune cells to interact directly with ACE points was blocked, the severity of infection was reduced. "The immune system uses molecules to communicate that cross from the brain into the dura mater," said Kipnis. "This crossing needs to be tightly regulated, otherwise detrimental effects on brain function can occur." Reich and his team also observed an interesting connection between the participants' age and the leakiness of ACE points. In older participants, more dye leaked into the surrounding fluid and space around the blood vessels. "This might point to a slow breakdown of the ACE points over the course of aging," said Reich, "and this could be consequential in that the brain and immune system can now interact in ways that they're not supposed to." The connection to aging and the disruption of a barrier separating the brain and immune system fits with what has been observed in aging mice and in autoimmune disorders like multiple sclerosis. This newfound link between the brain and immune system could also help explain why our risk for developing neurodegenerative diseases increases as we get older, but more research is needed to confirm this connection. This study was supported by the NINDS Intramural Research Program, the National Institute on Aging (AG034113, AG057496, AG078106), and the Cure Alzheimer's Fund BEE Consortium.

We all know someone who's had a head injury that was 'only' a concussion, but even mild traumatic brain injuries can cause lasting damage, and the vast majority are never diagnosed. A team created a way to diagnose mild TBIs (mTBIs) even when MRI scans showed nothing, using the body's own immune cells called macrophages. They attached microparticle 'backpacks' containing a common MRI contrast agent to the cells, which migrated to the brain and allowed them to see evidence of inflammation in pigs with a mock mTBI. Researchers have created a new brain imaging method that allows mild traumatic brain injuries (mTBIs) to be diagnosed, even when existing imaging techniques like magnetic resonance imaging (MRI) don't show any structural abnormalities. The technique involves loading gadolinium, a standard MRI contrast agent, into hydrogel-based micropatches that are attached to immune cells called macrophages. mTBIs cause inflammation in the brain, which produces signals that attract macrophages to migrate there. Coupling the gadolinium contrast agent to these cells enables MRI to reveal brain inflammation and increase the number of correctly diagnosed mTBI cases, improving patient care. The method is described in a new paper in Science Translational Medicine. "70-90% of reported TBI cases are categorized as 'mild,' yet as many as 90% of mTBI cases go undiagnosed, even though their effects can last for years and they are known to increase the risk of a host of neurological disorders including depression, dementia, and Parkinson's disease," said senior author Samir Mitragotri, Ph.D., in whose lab the research was performed. "Our cell-based imaging approach exploits immune cells' innate ability to travel into the brain in response to inflammation, enabling us to identify mTBIs that standard MRI imaging would miss." Mitragotri is a Core Faculty member of the Wyss Institute at Harvard University and the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard's John A. Paulson School of Engineering and Applied Sciences (SEAS). Using immune cells to identify inflammation Most of us know someone who has had a concussion (another name for an mTBI), sometimes even more than one. But the vast majority of people who experience an mTBI are never properly diagnosed. Without that diagnosis, they can exacerbate their injuries by returning to normal activity before they're fully recovered, which can lead to further damage. Some studies even suggest that repeated mTBIs can lead to chronic traumatic encephalopathy (CTE), the neurodegenerative disease that has been found to afflict more than 90% of professional American football players. Because the effects of mTBI are believed to be caused by "invisible" brain inflammation, members of the Mitragotri lab decided to leverage their experience with immune cells to create a better diagnostic. "Our previous projects have focused on controlling the behavior of immune cells or using them to deliver drugs to a specific tissue. We wanted to exploit another innate ability of immune cells -- homing to sites of inflammation in the body -- to carry imaging agents into the brain, where they can provide a visible detection signal for mTBI," said first author Lily Li-Wen Wang, Ph.D.. Wang is a former Research Fellow in the Mitragotri Lab at the Wyss Institute and SEAS who is now a scientist at Landmark Bio. The team planned to use their cellular backpack technology to attach gadolinium molecules to macrophages, a type of white blood cell that is known to infiltrate the brain in response to inflammation. But right away, they ran into a problem: in order to function as a contrast agent for MRI scans, gadolinium needs to interact with water. Their original backpack microparticles are compost of a polymer called PLGA, which is hydrophobic (meaning it repels water). So Wang and her co-authors started developing a new backpack made out of a hydrogel material that could be manufactured at a large scale in the lab. After years of hard work, they finally created a new hydrogel backpack that could produce a strong gadolinium-mediated MRI signal, attach stably to both mouse and pig macrophages, and maintain their cargo for a sustained period of time in vitro. They named their new microparticles M-GLAMs, short for "macrophage-hitchhiking Gd(III)-Loaded Anisotropic Micropatches." Now, it was time to test them in a more realistic setting, for which they partnered with researchers and clinicians at Boston Children's Hospital. First, they injected mouse M-GLAMs macrophages into mice to see if they could visualize them in vivo. They were especially interested to see if they accumulated in the kidney, as existing gadolinium-based contrast agents like Gadavist® can cause health risks for patients with kidney disease. Their M-GLAMs did not accumulate in the mice's kidneys, but persisted in their bodies for over 24 hours with no negative side effects. In contrast, mice injected with Gadavist® showed substantial accumulation of the contrast agent in their kidneys within 15 minutes of injection, and the substance was fully cleared from their bodies within 24 hours. Then, they tested porcine M-GLAMs in a pig model of mTBI. They injected the M-GLAMs into the animals' blood two days after a mock mTBI, then used MRI to evaluate the concentration of gadolinium in the brain. They focused on a small region called the choroid plexus, which is known as a major conduit of immune cells into the brain. Pigs that received the M-GLAMs displayed a significant increase in the intensity of gadolinium present in the choroid plexus, while those injected with Gadavist® did not, despite confirmation of increased inflammation macrophage density in the brains of both groups. The animals showed no toxicity in any of their major organs following administration of the treatments. "Another important aspect of our M-GLAMs is that we are able to achieve better imaging at a much lower dose of gadolinium than current contrast agents -- 500-1000-fold lower in the case of Gadavist®," said Wang. "This could allow the use of MRI for patients who are currently unable to tolerate existing contrast agents, including those who have existing kidney problems." The authors note that while M-GLAMs can indicate the presence of inflammation in the brain via the high concentration of macrophages entering it through the choroid plexus, their technique cannot pinpoint the exact location of injuries or inflammatory responses in brain tissue. However, if coupled with new treatment modalities like one they developed in , M-GLAMS could offer a more rapid and effective way to identify and reduce inflammation in mTBI patients to minimize damage and speed their recovery. The researchers have submitted a patent application for their technology, and hope to be able to bring it to the market in the near future. They are currently exploring collaborations with biotech and pharmaceutical companies to accelerate it to clinical trials . "This work demonstrates just how much potential is waiting to be unlocked within the human body for a variety of functions: monitoring health, diagnosing problems, treating diseases, and preventing their recurrence. I'm impressed with this team's ingenuity in leveraging immune cells to improve medical imaging, and hope to see it in clinicians' hands soon," said Wyss Founding Director Donald Ingber, M.D., Ph.D. Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS. Additional authors of the paper include Yongsheng Gao, Vineeth Chandran Suja, Suyong Shaha, Rick Liao, Ninad Kumbhojkar, Supriya Prakash, Kyung Soo Park, and Michael Dunne from the Wyss Institute and SEAS; Masen Boucher, Kaitlyn Warren, Camilo Jaimes, and Rebekah Mannix from Boston Children's Hospital; Neha Kapate and Morgan Janes from the Wyss Institute, SEAS, and MIT; Bolu Ilelaboye, Andrew Lu, and Solomina Darko from SEAS; and former SEAS members Tao Sun and John Clegg. This research was supported by the US Department of Defense under Grant No. W81XWH-19-2-0011 and the National Science Foundation Graduate Research Fellowship under Grant Nos. 1122374 and 1745302.