What’s New in Research: June 2023

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 cardiovascular diseaes and stress in neurons, biomarkers for glaucoma, long COVID and chronic fatigue syndrome, pesticides and Parkinson’s disease, brain network connections for anosognosia, mutations in the noncoding genome and more.

New Model Offers Insights into How Stress in Neurons Connects to Cardiovascular Disease

Thomas Michel

Oxidative stress – characterized by elevated levels of unstable molecules called reactive oxygen species– is associated with neurodegeneration and cardiovascular disease. However, until recently it has not been possible to demonstrate a causal relationship between oxidative stress and disease states. A new study used “chemogenetics” to activate a recombinant yeast protein expressed in mouse tissues to manipulate levels of oxidative stress in living mice. Researchers from Brigham and Women’s Hospital, Harvard Medical School, and the Novartis Institutes for Biomedical Research applied chemogenetic approaches in a new transgenic mouse model to introduce oxidative stress into blood vessels and neurons.

The researchers initially set out to use this new transgenic mouse model to identify pathways through which oxidative stress might cause dysfunction of blood vessels and lead to diseases like hypertension and aortic aneurysms. But they were surprised to find that these mice rapidly developed profound ataxia, characterized by an inability to walk. Probing further, they found that specific sets of sensory neurons in peripheral nerve cells had undergone degeneration from oxidative stress caused by the transgene. And when the researchers looked at the hearts of these animals, they found that heart muscle had developed cardiac hypertrophy. This combination of sensory neuron degeneration and cardiac hypertrophy is associated with Friedreich’s ataxia (FA), a progressive neurodegenerative disease that is the most common form of hereditary ataxia found in patients. Researchers also characterized specific inflammatory cell types involved in these responses, offering a more complete understanding of the mechanisms through which FA causes cardiac hypertrophy.

“Our team followed up on an unexpected phenotype that we uncovered in a new transgenic mouse line and found surprising new connections between peripheral nerves and the heart,” said Thomas M. Michel, MD, PhD of the Brigham Division of Cardiovascular Medicine. “Our findings may help us understand the cardiac remodeling seen in the hearts of patients with neurodegenerative diseases.”

Higher Levels of Diglycerides and Triglycerides Adversely Associated with Glaucoma

Oana Zeleznik, Jae H. Kang, Louis Pasquale

Glaucoma is the leading cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG) is the most common form, and yet the cause of this disease is poorly understood. Findings from previous genome-wide association studies suggest that there is a complex metabolic network that affects optic nerve health. Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, and the Department of Ophthalmology at the Icahn School of Medicine at Mount Sinai aimed to identify plasma metabolites associated with risk of developing POAG in a case-control study nested within the prospective Nurses’ Health Studies and the Health Professionals Follow-Up Study. This study included 599 participants who developed POAG and 599 matched controls and examined pre-diagnostic circulating plasma metabolites from approximately 10 years before POAG diagnosis. To confirm the findings, the researchers evaluated the metabolomic data in plasma samples of 2,238 glaucoma cases and 44,723 controls from the UK Biobank. They found that higher levels of diglycerides and triglycerides were associated with risk of glaucoma, suggesting that they play an important role in glaucoma pathogenesis.

“Our study is the first to assess associations between pre-diagnostic circulating metabolites and POAG risk in two large independent datasets,” said co-first authors Oana A. Zeleznik, PhD, and Jae H. Kang, ScD, investigators at Brigham’s Channing Division of Network Medicine. “These results provide new insights into the etiology of POAG. Our data implicate dysregulation in lipid metabolism and mitochondrial function in glaucoma etiology and suggest new targets for glaucoma prevention or therapies,” said senior author Louis R. Pasquale, MD, Professor of Ophthalmology at the Icahn School of Medicine at Mount Sinai.

Study Identifies Brain Network Connections Associated with Anosognosia

Isaiah Kletenik

Anosognosia is a condition in which a patient is unaware of their neurological deficit or psychiatric condition. Visual anosognosia, also called Anton syndrome, is associated with complete cortical blindness and unawareness of vision loss. Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, sought to identify brain network connections associated with anosognosia. The investigators analyzed the connectivity patterns of 267 lesion locations associated with either vision loss (with and without awareness) or weakness (with and without awareness). Researchers used a recently validated technique termed lesion network mapping to test whether these lesion-induced deficits map to specific brain networks. They were able to identify distinct network connections associated with visual anosognosia and motor anosognosia as well as a shared network for awareness of these deficits. The visual anosognosia network was defined by connectivity to visual and metacognitive processing regions while the shared network for awareness converged on the hippocampus and precuneus—brain structures that are associated with memory.

“Despite being described more than 100 years ago, visual anosognosia has had little formal analysis,” said corresponding author Isaiah Kletenik, MD, an investigator at Brigham’s Division of Cognitive and Behavioral Neurology and the Center for Brain Circuit Therapeutics. “Our results are the first to identify the role of the hippocampus in a systematic analysis of visual anosognosia. Memory-associated structures are necessary to recognize a deficit by comparing visual inputs to prior information stored in memory while updating self-knowledge about performance compared to previous abilities.”

Similar Symptoms, Biological Abnormalities Underlie Long COVID and Chronic Fatigue Syndrome

Anthony Komaroff

Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome are debilitating conditions with similar symptoms. Neither condition has diagnostic tests or treatments approved by the Food and Drug Administration (FDA) and each cost the United States billions of dollars each year in direct medical expenses and lost productivity. Doctors and researchers have wondered what are the underlying biological abnormalities that may cause symptoms, and whether these abnormalities are similar in the two illnesses.

A review article authored by senior investigators at Brigham and Women’s Hospital and Harvard Medical School, and the Mailman School of Public Health and Vagelos College of Physicians and Surgeons of Columbia University, addresses these questions. In it, the authors review 559 scientific publications. The authors compared the symptoms of both conditions, noting their great similarity, and then showed that very similar underlying biological abnormalities have been found in both conditions, abnormalities involving the brain, immune system, heart, lungs, gut, and energy metabolism.

“By making a side-by-side comparison of what is known about each type of abnormality, in each of these two illnesses, our review serves as a ‘road map’ to identify areas that require further research,” said Anthony L. Komaroff, MD, senior physician in the Brigham Department of Medicine and professor of medicine at Harvard Medical School. “We hope that identifying those abnormalities for which the evidence is strongest will help focus the search for improved diagnostic tests and effective treatments.”

Bench-to-Field Study Identifies Pesticides That Could Influence Parkinson’s Disease

Vikram Khurana

Richard Krolewski

A new study from researchers in the Khurana lab at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, in close collaboration with researchers from the Ritz lab at UCLA and the Rubin lab at Harvard University, identified pesticides that could be relevant to the development of Parkinson’s disease. The study was led by Richard Krolewski, MD, PhD, a neurologist in the Brigham’s Division of Movement Disorders and Ann Romney Center for Neurologic Diseases, and Kimberly Paul, PhD, from UCLA, along with collaboration with Edinson Lucumi Moreno within the Khurana lab at the Brigham.

Both genetic and environmental factors may influence the likelihood of developing Parkinson’s disease. Using agricultural records, the researchers investigated 288 pesticides, finding that long-term exposure to 53 of these pesticides was associated with Parkinson’s disease. The team then used a screening system in dopamine neurons derived from Parkinson’s patients to study 39 of those pesticides and identified 10 that were directly toxic to dopamine neurons. The study also found exposure to multiple pesticides used in combination, such as in cotton farming, is more toxic to dopamine neurons than any single pesticide.

“The combination of bench science and epidemiology is quite novel here,” said Krolewski. “The bench science is able to address questions that are difficult to answer with epidemiology while the epidemiology helps direct the bench science – the sum is greater than the parts.”

The Department of Defense supported this project and has now supported the group to utilize diverse stem-cell models derived from Parkinson’s patients to investigate how pesticides and the gut microbiome disrupt key neuronal processes affecting both movement and cognition.

“The findings advance a major goal of the BWH Movement Division to tailor therapies to specific triggers of Parkinson’s in each patient,” said Khurana.

Computational Method Uncovers the Effects of Mutations in the Noncoding Genome

Martha Bulyk

Less than two percent of the human genome codes for proteins, with the rest being noncoding and likely helping with gene regulation. Mutations in the noncoding genome often trigger trait changes that cause disease or disability by altering gene expression. However, it can be hard for scientists to track down which of numerous variants associated with a disease or other complex trait are the causal ones and to understand the mechanism of their effects. Researchers at the Brigham developed a new computational approach that hones in on small regions of the noncoding genome that genome-wide association studies (GWAS) identified as being correlated with changes to blood cell traits, including lowered lymphocyte counts and hemoglobin concentrations. They then scanned these regions for specific mutations that caused a transcription factor protein, called PU.1, to bind to certain areas more or less strongly than normal, and examined the effect that such mutations had on PU.1’s binding site. Their method uncovered 69 mutations that affected PU.1 binding and were related to quantitative differences in blood cell trait changes, 51 of which altered PU.1’s binding site and thus likely caused a physiological difference.

“Our method could be applied to better understand a range of genetic conditions and to help pinpoint the causal variants in the noncoding genome underlying various biomedical traits,” said senior author Martha Bulyk, PhD, a Principal Investigator in the Brigham’s Division of Genetics. “Here, we identified noncoding variants that appear to contribute to quantitative differences in blood cell trait changes. This approach could be used to uncover the transcriptional regulatory mechanisms hidden in the GWAS data of other complex traits.”

Variations in Kidney Function on Transition to Sacubitril/Valsartan Not Consistently Associated with Adverse Clinical Outcomes

Early reductions in kidney function associated with heart failure therapies are a common clinical concern which may lead to premature discontinuation of these beneficial drugs. However, little is known about the prognostic implications of post-initiation changes in estimated glomerular filtration rate (eGFR) with sacubitril/valsartan.

A new analysis led by investigators from Brigham and Women’s Hospital evaluated the association between a moderate eGFR decline (>15 percent) after transition to sacubitril/valsartan on the development of subsequent cardiovascular outcomes and long-term treatment benefits in patients with chronic heart failure. The investigators carried out a secondary analysis of two large-scale clinical trials that enrolled heart failure patients, known as the PARADIGM-HF and PARAGON-HF trials. They found that eGFR decline on transition to sacubitril/valsartan occurred in approximately 1 in 10 patients, was usually mild and partially recovered in most patients.

Importantly, moderate eGFR decline upon transition to sacubitril/valsartan did not consistently portend adverse prognostic significance in patients with heart failure with reduced or preserved ejection fraction, measures of two distinct forms of the diagnosis. Furthermore, the long-term treatment benefits of sacubitril/valsartan were retained across a range of acute early eGFR declines. However, the authors note that the implications of post-transition eGFR changes in patients with severe chronic kidney disease and in those experiencing more extreme reductions in renal function are less clear as these patients were excluded in both trials.

“This study helps to address a major perceived barrier to the implementation of this drug in patients with chronic heart failure” said lead author Safia Chatur, MD, of the Cardiovascular Division at the Brigham who presented findings from the study in a highlighted original research session featuring top oral abstracts at the American College of Cardiology conference in early March. “The occurrence of moderate reductions in renal function when transitioning patients to sacubitril/valsartan should not deter drug continuation or stall up-titration.”

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