Check out “What’s New in Research” to find out about discoveries and advancements from Brigham researchers. This month, we feature new research from Brigham researchers on areas most in need of stroke resources, brain lesions associated with memory loss, a novel technology for detecting immunothrombosis, preventing immune damage and reducing graft dysfunction after lung transplant, an immune response underlying inflammatory arthritis that results from cancer therapy, a nanoprobe for diabetic retinopathy and more.  

New Study Identifies Areas in Most Need for Stroke Resources

Joshua Bernstock

Globally, stroke is one of the leading causes of suffering in humans. In reports from 2019, 12 million people worldwide suffered a stroke, which resulted in 7 million deaths. The disease burden of stroke has a significant economic impact, especially in low- and middle-income countries and locations with large aging populations. Understanding the burden of stroke and its macroeconomic impact is vital to allocate resources adequately to areas most affected by the disease.

Investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, analyzed the global, regional, and national macroeconomic impact of stroke and its subtypes: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The team used available 2019 data from 173 countries. The authors created a novel formula using a value of lost welfare approach. The team analyzed disability-adjusted life year data for stroke and its subtypes from the 2019 Global Burden of Disease database and the gross domestic product data from the World Bank. The gross domestic product and disability-adjusted life year data were then combined to estimate the macroeconomic losses. Their results identify which countries and regions need stroke-related resources the most, finding that a disproportionate stroke burden falls on low-to-middle income countries.

“This study is meant to highlight the economic burden of the disease,” said corresponding author Joshua Bernstock, MD, PhD, MPH, from the Department of Neurosurgery. “In doing so, we hope resources for stroke are allocated appropriately globally. Stroke can have vast economic consequences but there are cost-effective interventions. We hope that our data help to inform policies on stroke care and prevention to reduce this burden.”

Read more in Stroke.

Brain Lesions Associated with Memory Loss in Multiple Sclerosis Linked to Common Brain Circuit

Isaiah Kletenik

Between 30 to 50 percent of people living with multiple sclerosis (MS) will experience memory problems but the cause is uncertain. Brain lesions are the hallmark imaging sign used to diagnose MS and are often associated with memory dysfunction. However, increased MS brain lesions are not specific to memory problems and are also associated with fatigue, walking difficulty and other common MS symptoms. Previous studies that attempted to align the anatomy of lesions associated with memory problems in MS led to conflicting results.

Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, conducted a study to figure out which MS lesion locations are associated with memory issues. The team, led by Isaiah Kletenik, MD, analyzed imaging and cognitive data from 431 people with MS enrolled in the Comprehensive Longitudinal Investigation of MS at Brigham and Women’s Hospital, or CLIMB study. Researchers mapped white matter lesion locations from each person and tested associations between memory dysfunction and a memory circuit previously derived from strokes causing memory problems. They found that MS lesions that were associated with memory problems intersected with this memory circuit centered on the hippocampus. The researchers also analyzed the MS lesion locations compared to large functional and structural brain atlases to identify unique MS memory circuits.

“In many neurologic diseases, we know what brain function will be disrupted based on the location of lesions, but in MS, the lesions are widespread making localization challenging,” Kletenik said. “By applying a circuit-based approach, we show that lesions associated with MS memory dysfunction connect to a memory circuit.”

The team included researchers from the Brigham MS Center and from the Center for Brain Circuit Therapeutics led by Michael D. Fox, MD, PhD. Rohit Bakshi, MD, Bonnie Glanz, PhD, Charles Guttmann, MD, and Tanuja Chitnis, MD, collected neuroimaging and behavioral data on people with MS as part of large, ongoing studies at the Brigham MS Center. Dr. Bakshi and Dr. Guttmann developed an imaging pipeline to automatically segment MS lesions and Dr. Glanz worked with MS Center staff to perform cognitive testing for this study.

Read more about the common brain circuit linked to MS memory loss in Journal of Neurology.

Researchers Develop Novel Technology to Quantify Protein Critical to Blood Clot Formation through Breath Gas Analysis

Ali Hafezi-Moghadam

Immunothrombosis, or the formation of microscopic blood clots during inflammation, is a major cause of morbidity among patients with sepsis or severe COVID-19. A key enzyme in this process is thrombin. To date, no method exists for early detection of immunothrombosis in a living organism.

A team of investigators led by Ali Hafezi-Moghadam, MD, PhD, director of the Molecular Biomarkers Nano-Imaging Laboratory (MBNI) at Brigham and Women’s Hospital, a founding member of Mass General Brigham healthcare system, and an associate professor of Radiology at Harvard Medical School, developed a novel technology to diagnose immunothrombosis by measuring thrombin activity through breath gas. The researchers generated hyperbranched polymeric nanoprobes, containing thrombin-sensitive regions bound to reporter molecules that would become gaseous upon liberation. Thrombin in microvessels of animals with immunothrombosis liberated the volatile reporter that was then exhaled through the lungs. Gas biopsies, or samples from the exhaled breath, were analyzed in gas chromatography mass spectrometry to deduce the intravascular thrombin activity. These results lay groundwork for clinical translation.

“Early diagnosis of immunothrombosis and intervention could prevent organ failure in patients with sepsis or severe COVID-19,” said Hafezi-Moghadam. “Our technology provides unprecedented knowledge of key enzymatic activity anywhere in the body. Such real-time measurement has the potential to improve personalized and precision treatments and save lives.”

Read more in Advanced Materials. This work was supported by NIH Impact Award (DK108238-01), and JDRF Innovation Award (INO-2016-222-A-N).

Naturally Occurring Compound in Body Can Prevent Immune Damage and Reduce Graft Dysfunction After Lung Transplant

Charles Serhan

Ischemic reperfusion injuries (IRI) are a frequent and morbid complication after lung transplants that occur when blood flow is temporarily stopped and restarted. Until recently, little has been understood about the early immune response that gives rise to these injuries. Researchers at Brigham and Women’s Hospital, in collaboration with Daniel Kreisel, MD, PhD, and colleagues at Washington University School of Medicine in St. Louis, found that the body produces a lipid mediator called Resolvin D1 (RvD1) which can dampen the body’s immune response, and prevent IRI organ damage after tissue transplantation.

The research team looked at human and murine lung grafts immediately after transplantation, and identified that naturally occuring RvD1 levels increased. Next, they prepared an RvD1 treatment and found that it limited a type of immune cell—neutrophils—from infiltrating and swarming in lung transplant models with IRI, thereby reducing early graft dysfunction. Finally, researchers used single-cell RNA sequencing to compare donor and recicipient immune cells from lung grafts after RvD1 treatment, and found that immune cells started expressing fewer inflammatory genes. Together, their results show that RvD1 contributes to a protective regulatory pathway that can prevent IRI-mediated graft dysfunction and reduce inflammation following transplantation.

“This cross-institutional collaboration allowed us to address tissue damage after lung transplants, which may be therapeutic in the clinic,”said co-senior author Charles N. Serhan, PhD, DSc, who is the Director of the Center for Experimental Therapuetics and Reperfusion Injurty at the Brigham. “In the future, we hope to test how RvD1 and other pro-resolving mediators born at BWH can strengthen other organ transplants and surgical procedures as well.”

Read more in PNAS.

Study Characterizes Unique Immune Response in Patients who Experience Inflammatory Arthritis as Side Effect of Cancer Therapies

Deepak Rao

Immune checkpoint inhibitor (ICI) therapies used to treat cancer come with the risk of adverse autoimmune responses, including arthritis that can persist for years and require joint replacement surgery. Little is known about the specific cells responsible for these events. Researchers at Brigham and Women’s Hospital and collaborators led a study to investigate these immune adverse events and identified a specific type of CD8 T cell that characterizes inflammatory arthritis induced by ICI therapies.

Researchers studied T cells from a patient with severe ICI-arthritis who required bilateral knee replacements. In addition to these two joint tissue samples, they studied the fluid that accumulates within joints from an additional 23 patients with this condition and compared these samples to samples from patients with two common autoimmune conditions, rheumatoid arthritis or psoriatic arthritis. By comparing protein and gene expression levels across diseases, they were able to characterize unique immunological features of the CD8 T cells in ICI-arthritis. They further identified that a specific set of cytokines, type I interferons, can promote the CD8 T cell activation seen in ICI-arthritis.

Patients whose cancer was treated with ICI had high levels of this CD8 T cell type, and additional analysis revealed that the cells traveled between the joints and blood. Further, the T cells persisted in the bloodstream, providing one explanation for why ICI-arthritis continues even after ICI therapy is discontinued. Limitations include a small cohort of patients who are taking various treatments. Further research is needed to characterize how the CD8 T cells contribute to joint inflammation.

“Our results suggest that ICI therapy gives rise to a unique population of CD8 T cells in patients who develop ICI-arthritis,” said co-corresponding author Deepak A. Rao, MD, PhD, of the Brigham’s Division of Rheumatology, Inflammation, Immunity. “The immune events we characterized differ dramatically from the typical responses we have seen in autoimmune diseases like rheumatoid arthritis and psoriatic arthritis.”

Read more in Science Immunology.

Novel Nanoprobe Developed to Detect Diabetic Retinopathy in Its Early Stages

Ali Hafezi-Moghadam

In a paper published by the research team of Ali Hafezi-Moghadam, MD, PhD at the Brigham and Women’s Hospital (BWH), a founding member of Mass General Brigham, authors introduced a biodegradable fluorescent nanoprobe to detect diabetic retinopathy (DR) in its early molecular stage. Retinopathy is a prevalent complication of diabetes and a cause of severe vision loss. Current clinical diagnosis relies on detection of irreversible structural damages. Early subclinical diagnosis and intervention could drastically improve prognosis for the rapidly growing population of individuals with diabetes.

The researchers had previously established fluorescent nanoprobes for molecular imaging and showed higher expression of the molecule VEGFR-2 in the eye during diabetes. Upon circulating in the bloodstream, the nanoprobes bind to VEGFR-2, expressed in the retinal microvessels. Visualizations of the nanoprobe interactions in live retinal microscopy reveal incipient DR in its earliest stage. The current work facilitates translation by making the nanoprobe both biodegradable and bright enough for in vivo detection. Fluorophores in close proximity self-quench, so to overcome this challenge a fluorophore with bulky side arms that keep the neighboring molecules at bay was synthesized and loaded into the nanoprobe. The outcome was a biodegradable nanoprobe with sufficient brightness capable of distinguishing early DR in mice.

“Early diagnosis of diabetic complications is an unmet medical need. We have overcome a key hurdle toward clinical translation of our molecular imaging approach.” said Hafezi-Moghadam, associate professor of Radiology at Harvard Medical School and director of the Molecular Biomarkers Nano-Imaging Laboratory (MBNI) at BWH. “Our new results set the stage for clinical testing of this tool in an effort to one day prevent vision loss in individuals with diabetes.”

Read more in the journal of Biosensors and Bioelectronics.

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