In the News

Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:

Featured Article

Here’s when your weight loss will plateau, according to science

CNN
Monday, April 22, 2024

Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.

In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using to drop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.

Researchers develop model for how the brain acquires essential omega-3 fatty acids

Findings may aid design of targeted drug delivery into the brain and central nervous system

Researchers at the National Institutes of Health and colleagues have developed a zebrafish model that provides new insight into how the brain acquires essential omega-3 fatty acids, including docosahexaenoic acid (DHA) and linolenic acid (ALA). Their findings, published in Nature Communications, have the potential to improve understanding of lipid transport across the blood-brain barrier and of disruptions in this process that can lead to birth defects or neurological conditions. The model may also enable researchers to design drug molecules that are capable of directly reaching the brain.

Omega-3 fatty acids are considered essential because the body cannot make them and must obtain them through foods, such as fish, nuts and seeds. DHA levels are especially high in the brain and important for a healthy nervous system. Infants obtain DHA from breastmilk or formula, and deficiencies of this fatty acid have been linked to problems with learning and memory. To get to the brain, omega-3 fatty acids must pass through the blood-brain barrier via the lipid transporter Mfsd2a, which is essential for normal brain development. Despite its importance, scientists did not know precisely how Mfsd2a transports DHA and other omega-3 fatty acids.

In the study, the research team provides images of the structure of zebrafish Mfsd2a, which is similar to its human counterpart. The snapshots are the first to detail precisely how fatty acids move across the cell membrane. The study team also identified three compartments in Mfsd2a that suggest distinct steps required to move and flip fatty acids through the transporter, as opposed to movement through a linear tunnel or along the surface of the protein complex. The findings provide key information on how Mfsd2a transports omega-3 fatty acids into the brain and may enable researchers to optimize drug delivery via this route. The study also provides foundational knowledge on how other members of this transporter family, called the major facilitator superfamily (MFS), regulate important cellular functions.

This model shows how docosahexaenoic acid (DHA) and other omega-3 fatty acids cross the blood-brain barrier through the lipid transporter Mfsd2a

Docosahexaenoic acid (DHA) is an essential omega-3 fatty acid that is important for a healthy nervous system. This model shows how DHA and other omega-3 fatty acids cross the blood-brain barrier through the lipid transporter Mfsd2a. Image credit: Ethan Tyler, NIH Medical Arts

IRP researchers identify large genetic changes that contribute to dementia risk

Discovery provides potential clues for Lewy body and frontotemporal dementias

Scientists at the National Institutes of Health have identified new genetic risk factors for two types of non-Alzheimer’s dementia. These findings were published in Cell Genomics and detail how researchers identified large-scale DNA changes, known as structural variants, by analyzing thousands of DNA samples. The team discovered several structural variants that could be risk factors Lewy body dementia (LBD) and frontotemporal dementia (FTD). The project was a collaborative effort between scientists at the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) at NIH.

Structural variants have been implicated in a variety of neurological disorders. Unlike more commonly studied mutations, which often affect one or a few DNA building blocks called nucleotides, structural variants represent at least 50 but often hundreds, or even thousands, of nucleotides at once, making them more challenging to study.

“If you imagine that our entire genetic code is a book, a structural variant would be a paragraph, page, or even an entire chapter that has been removed, duplicated, or inserted in the wrong place,” said Sonja W. Scholz, M.D., Ph.D., investigator in the neurogenetics branch of NINDS and senior author of this study.

IRP study identifies features of Long COVID neurological symptoms

Findings offer insight into biological mechanisms, pointing to possible treatments

Twelve people with persistent neurological symptoms after SARS-CoV-2 infection were intensely studied at the National Institutes of Health (NIH) and were found to have differences in their immune cell profiles and autonomic dysfunction. These data inform future studies to help explain persistent neurological symptoms in Long COVID. The findings, published in Neurology: Neuroimmunology & Neuroinflammation, may lead to better diagnoses and new treatments.

People with post-acute sequelae of COVID-19 (PASC), which includes Long COVID, have a wide range of symptoms, including fatigue, shortness of breath, fever, headaches, sleep disturbances, and 'brain fog,' or cognitive impairment. Such symptoms can last for months or longer after an initial SARS-CoV-2 infection. Fatigue and 'brain fog' are among the most common and debilitating symptoms, and likely stem from nervous system dysfunction.

Researchers used an approach called deep phenotyping to closely examine the clinical and biological features of Long COVID in 12 people who had long-lasting, disabling neurological symptoms after COVID-19. Most participants had mild symptoms during their acute infection. At the NIH Clinical Center, participants underwent comprehensive testing, which included a clinical exam, questionnaires, advanced brain imaging, blood and cerebrospinal fluid tests, and autonomic function tests.

The results showed that people with Long COVID had lower levels of CD4+ and CD8+ T cells — immune cells involved in coordinating the immune system’s response to viruses — compared to healthy controls. Researchers also found increases in the numbers of B cells and other types of immune cells, suggesting that immune dysregulation may play a role in mediating Long COVID.

Young men at highest risk of schizophrenia linked with cannabis use disorder

NIH study highlights the need to proactively screen for, prevent, and treat cannabis use disorder especially among young people

Young men with cannabis (marijuana) use disorder have an increased risk of developing schizophrenia, according to a study led by researchers at the Mental Health Services in the Capital Region of Denmark and the National Institute on Drug Abuse (NIDA) at the National Institutes of Health. The study, published in Psychological Medicineanalyzed detailed health records data spanning five decades and representing more than six million people in Denmark to estimate the fraction of schizophrenia cases that could be attributed to cannabis use disorder on the population level.

Researchers found strong evidence of an association between cannabis use disorder and schizophrenia among men and women, though the association was much stronger among young men. Using statistical models, the study authors estimated that as many as 30 percent of cases of schizophrenia among men aged 21-30 might have been prevented by averting cannabis use disorder.

Cannabis use disorder and schizophrenia are serious, but treatable, mental disorders that can profoundly impact people’s lives. People with cannabis use disorder are unable to stop using cannabis despite it causing negative consequences in their lives. Schizophrenia is a serious mental illness that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality, and the symptoms of schizophrenia can make it difficult to participate in usual, everyday activities. However, effective treatments are available for both cannabis use disorder and schizophrenia.

“The entanglement of substance use disorders and mental illnesses is a major public health issue, requiring urgent action and support for people who need it,” said NIDA Director and study coauthor Nora Volkow, M.D. “As access to potent cannabis products continues to expand, it is crucial that we also expand prevention, screening, and treatment for people who may experience mental illnesses associated with cannabis use. The findings from this study are one step in that direction and can help inform decisions that health care providers may make in caring for patients, as well as decisions that individuals may make about their own cannabis use.”

IRP researchers uncover new details on rare immune disease

Idiopathic CD4 lymphocytopenia leaves immune system vulnerable to other diseases, cancers

In an 11-year study, researchers at the National Institutes of Health have further characterized idiopathic CD4 lymphocytopenia (ICL), a rare immune deficiency that leaves people vulnerable to infectious diseases, autoimmune diseases and cancers. Researchers observed that people with the most severe cases of ICL had the highest risk of acquiring or developing several of the diseases associated with this immune deficiency. This study, published in the New England Journal of Medicine, was led by Irini Sereti M.D., M.H.S., and Andrea Lisco, M.D., Ph.D., of the HIV Pathogenesis Section in the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, and conducted at the NIH Clinical Center.

ICL is a condition marked by too few CD4+ T-cells, which are a type of white blood cell. The clinical definition of ICL is a CD4+ T-cell count of less than 300 cells per cubic millimeter (mm³) of blood for at least six weeks, in the absence of any disease or therapy associated with reduced white blood cells. Unlike HIV, a virus that suppresses the immune system if left untreated, there is no evidence that ICL is transmitted from person to person, and it has no known cause. There are limited therapeutic options for ICL.

In this observational study, the NIAID researchers quantified immune cells and noted the presence of opportunistic infections—infections that typically only affect people with suppressed immune systems—and other clinical conditions among 91 participant volunteers with ICL. The most prevalent opportunistic infections were human papillomavirus-related diseases (in 29 percent of participants), cryptococcosis (24 percent), molluscum contagiosum (9 percent), and mycobacterial diseases other than tuberculosis (5 percent). Participants with CD4+ T-cell counts below 100 cells per mm³ had a more than five-fold higher risk of opportunistic infections than those with CD4+ T-cell counts above 100 cells. Cancer risk was also higher in individuals with the lowest CD4+ T-cell counts, but the risk of autoimmune disease was lower.

Scanning electron micrograph of a human T cell from the immune system of a healthy donor

Scanning electron micrograph of a human T cell from the immune system of a healthy donor. In multiple sclerosis, certain kinds of T cells are involved in the immune system’s attack on the central nervous system. 

“Eat, Sleep, Console” reduces hospital stay and need for medication among opioid-exposed infants

Researchers have found the “Eat, Sleep, Console” (ESC) care approach to be more effective than using the Finnegan Neonatal Abstinence Scoring Tool (FNAST) to assess and manage opioid-exposed newborns, according to a national, randomized controlled clinical trial funded by the National Institutes of Health. Newborns cared for with ESC were medically ready for discharge approximately 6.7 days earlier and 63% less likely to receive medication as part of their treatment, compared to newborns cared for with FNAST. ESC prioritizes non-pharmacologic approaches to care, such as a low-stimulation environment, swaddling, skin-to-skin contact and breastfeeding. ESC also encourages parental involvement in the care and assessment of their infants. These findings are based on the hospital outcomes of a large and geographically diverse group of opioid-exposed infants. A two-year follow-up study of a subset of infants is ongoing. The current findings are published in the New England Journal of Medicine.

“Medical care for newborns who were exposed to opioids during pregnancy varies widely across hospitals,” said Diana W. Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which co-led the study with the NIH Environmental Influences on Child Health Outcomes (ECHO) Program. “These findings are an important step toward standard, evidence-based guidance for the care of these infants.”

Opioid-exposed newborns may develop symptoms of neonatal opioid withdrawal syndrome (NOWS), which includes tremors; excessive crying and irritability; and problems with sleeping and feeding. For the past 50 years, FNAST has been the traditional assessment tool for infants with NOWS. FNAST is an extensive scoring system that assesses signs of withdrawal in more than 20 areas. Concerns have been raised about its subjectivity and overestimation of the need for opioid medication.

IRP study finds that immunotherapy substantially increases survival of people with lymphomatoid granulomatosis

Results from a clinical trial conducted by researchers at the National Institutes of Health (NIH) show that people with low-grade lymphomatoid granulomatosis who are treated with interferon alfa-2b, a type of immunotherapy, can live for decades after diagnosis. Lymphomatoid granulomatosis is a rare precancerous condition triggered by Epstein-Barr virus infection. Left untreated, the disease can progress to a high-grade form, which has a poorer prognosis and can quickly turn into an aggressive and fatal B-cell lymphoma.

In the phase 2 trial, led by researchers in the Center for Cancer Research at the National Cancer Institute (NCI), part of NIH, patients treated with interferon alfa-2b lived for a median of about 20 years. By contrast, past studies reported a median survival of less than two years for people with lymphomatoid granulomatosis.

The findings suggest that immunotherapy can prevent the progression of low-grade disease to high-grade disease. The results were published March 31, 2023, in Lancet Haematology.

“We have shown in this rare disorder that using a novel immunotherapy-based approach for low-grade disease is effective and improves survival compared with historical treatments such as chemotherapy and corticosteroids,” said Christopher J. Melani, M.D., of NCI’s Center for Cancer Research, who co-led the study. “I think the results of this study represent a significant contribution to determining the standard-of-care treatment for this rare disease.”

comparison of chest CT scans pre- and post-treatment with interferon alfa-2b

Treatment with interferon alfa-2b led to the disappearance of a large lesion (top image) in the lungs of a patient with lymphomatoid granulomatosis, as shown in this computed tomography chest scan.

Therapy for Rare Bone Disorder Shows Promise in NIH Clinical Trial

Medication is the first to reduce bone-weakening process in patients with fibrous dysplasia

A clinical trial at the National Institutes of Health found that a medication, denosumab, significantly reduced abnormal bone turnover in adults with fibrous dysplasia, a rare disease marked by weak and misshapen bones. Bone turnover, a process in which old bone is continuously replaced with new bone, is unusually accelerated in fibrous dysplasia and contributes to bone abnormalities. The study of eight participants was carried out by researchers from the National Institute of Dental and Craniofacial Research (NIDCR) and the NIH Clinical Center. The results, which showed that denosumab may improve patients’ quality of life by enabling healthy bone formation, were published as a correspondence report in the New England Journal of Medicine.

Fibrous dysplasia stems from gene mutations that cause scar-like (fibrous) tissue to replace healthy bone starting in early childhood. These fibrous lesions, which are marked by accelerated bone turnover, weaken bones, leading to bone deformities, fractures, physical disabilities, and pain. In some cases, the lesions can press up against organs and nerves, impairing functions like vision and breathing.

“Surgery is still the standard treatment for fractures and deformities caused by fibrous dysplasia,” said senior author Alison Boyce, M.D., a clinical investigator at NIDCR. “Denosumab is the first medication that appears to affect how fibrous dysplasia lesions behave and improves patients’ disease outcomes.”

Bone scans of a patient before (left) and after (right) a six-month denosumab treatment show reduced turnover within fibrous dysplasia lesions (dark-colored patches)

Bone scans of a patient before (left) and after (right) a six-month denosumab treatment show reduced turnover within fibrous dysplasia lesions (dark-colored patches).

Extremely rare gene variants point to a potential cause of age-related macular degeneration

A study from the National Eye Institute (NEI) identified rare genetic variants that could point to one of the general mechanisms driving age-related macular degeneration (AMD), a common cause of vision loss in older adults. The variants generate malformed proteins that alter the stability of the membrane attack complex (MAC), which may drive a chronic inflammatory response in the retina. The findings, published in the journal iScience, point to MAC as a potential therapeutic target to slow or prevent the development of AMD. NEI is part of the National Institutes of Health.

There are many known genetic variants that raise or lower an individual’s risk of getting AMD; however, the contribution of each of these genetic changes to AMD is small.

To discover genetic variants — and proteins — with a direct tie to the disease, Anand Swaroop, Ph.D., chief of NEI’s Neurobiology, Neurodegeneration and Repair Laboratory, and lead author of the study, undertook a collaboration with Michael Klein, M.D., a leading AMD clinician at the Oregon Health Sciences University (OHSU), Portland. Klein has collected clinical information for hundreds of patients, as well as families with a high number of individuals with AMD. Swaroop, Klein and colleagues looked for families carrying very rare AMD-causing variants, where the effect of the gene variant is very strong, and where the variant directly affects protein structure and function. This type of rare variant can reveal the root cause of disease.

FDA-approved drug shows promise in lab models for blinding childhood disease

Strategy may speed delivery of therapeutic options relative to time it would take to develop gene therapies

A National Institutes of Health team has identified a compound already approved by the U.S. Food and Drug Administration that keeps light-sensitive photoreceptors alive in three models of Leber congenital amaurosis type 10 (LCA 10), an inherited retinal ciliopathy disease that often results in severe visual impairment or blindness in early childhood.

LCA 10 is caused by mutations of the cilia-centrosomal gene (CEP290). Such mutations account for 20% to 25% of all LCA — more than any other gene. In addition to LCA, CEP290 mutations can cause multiple syndromic diseases involving a range of organ systems.

Using a mouse model of LCA10 and two types of lab-created tissues from stem cells known as organoids, the team screened more than 6,000 FDA-approved compounds to identify ones that promoted survival of photoreceptors, the types of cells that die in LCA, leading to vision loss. The high-throughput screening identified five potential drug candidates, including Reserpine, an old medication previously used to treat high blood pressure.

diagram showing how reserpine keeps light-sensitive photoreceptors alive in models of Leber congenital amaurosis type 10

In LCA10, CEP290 mutations lead to defects in the photoreceptor outer segment. Consequently, the building blocks of the primary cilium accumulate in the photoreceptors, which activates autophagy (shown left, untreated). Reserpine restores the balance between autophagy and the ubiquitin-proteasome system histone deacetylase 6 and improves primary cilium assembly. 

Continue Exploring the IRP

This page was last updated on Monday, April 22, 2024