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NIH-FUNDED EFFORTS CENTER ON HOW MICRORNAS REGULATE WOMEN’S HEALTH

Source: Brigham and Women's Hospital
Date: 6/24/2021
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Clinical studies for new drugs and vaccines, including the recent trials that led to the approval of COVID-19 vaccines, generally exclude women who are pregnant or lactating. For that reason, little is known about how hormonal changes affect drug pharmacokinetics and pharmacodynamics.

The National Institutes of Health (NIH) is supporting new efforts to address the shortage of research in this area. A team from Brigham and Women’s Hospital recently received two grants, which together total over $4.2 million, to look at various aspects of this connection. One grant is focused on drug metabolism and transport in pregnant and lactating women. The other is looking at predictors of HIV risk in women of reproductive age, a related area of research that also traditionally has been underfunded. Both are studying the role of noncoding microRNAs and how they lead to epigenetic changes in the body.

“There is a huge gap in knowledge, and the NIH has recognized the importance of shedding light on these topics,” said Raina Fichorova, MD, PhD, director of the Laboratory of Genital Tract Biology at the Brigham and Harvard University, who is leading the projects related to these grants. “Our group has a lot to contribute, because we already have a huge cohort of specimens that have been collected as part of our earlier work.”

The team has hundreds of samples from women’s health clinics in Zimbabwe and Uganda as well as clinics in the United States. Fichorova’s group has received approval for secondary use of the biospecimens, which include serum, vaginal and cervical samples collected in different stages of pregnancy and lactation as well as at different parts of the menstrual cycle.

Focusing on Mechanisms That Underlie Biological Change

Some of Dr. Fichorova’s previous research looked at the effect of reproductive hormones on women’s susceptibility to infection. One of the two new projects is taking a deeper look at the mechanisms that underlie the changes in infection susceptibility, including how the mucosal environment in the reproductive tract contributes to systemic factors. This includes the role of the microbiota in addition to differences in hormone levels.

“Our hypothesis is that noncoding microRNAs that are being released from the mucosal environment affect susceptibility to infection at the systemic level,” Dr. Fichorova said. “The mucus membrane releases vesicles containing these microRNAs, which are like little bullets of information. They travel through the blood circulation and are taken up by distant sites in the body.”

The study will investigate how these microRNAs act on the immune response, both directly and indirectly. First results were presented at the international Conference on Retroviruses and Opportunistic Infections, and manuscripts and data sharing have been prepared for submission in this funding period.

Characterizing Metabolic Changes

Many of the existing biospecimens that the lab has collected for its study of infection susceptibility, including vaginal swabs and serum samples, will also be used in the research related to drug metabolism. By characterizing the content of the microRNA in extracellular vesicles and how that content fluctuates in relation to pregnancy and breastfeeding, the researchers will be able to identify changes that are influenced by hormone levels as well as the makeup of the microbiota in the vaginal tract.

“MicroRNAs are one way to epigenetically control which proteins are actually manufactured by our bodies, and proteins are what ultimately determines phenotype,” Dr. Fichorova said. “Through these microRNA-containing vesicles, the hormonal environment and the microbial environment interact with each other, and they have an effect on the rest of our bodies, including how they use drugs.”

The study of microRNAs, she added, can also help to illuminate whether drugs are safe for the babies of pregnant women by revealing information about receptors and transporters that are specific to the placenta.

“We have multiple samples from each woman, which will allow us to translate findings and make many kinds of connections,” she concluded. “It’s really a goldmine of data that we hope many other researchers will find useful as well.”

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ADDRESSING QUESTIONS RELATED TO BRAIN HEALTH AND HEALTH CARE DISPARITIES AFTER HEMORRHAGIC STROKE

Source: Brigham and Women's Hospital
Date: 6/7/2021
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A team that includes investigators from Brigham and Women’s Hospital, Massachusetts General Hospital and Boston University School of Medicine is one of three multidisciplinary groups that recently received funding from the Henrietta B. and Frederick H. Bugher Foundation to develop breakthroughs related to hemorrhagic stroke. The over $11 million gift, which the American Heart Association is overseeing, aims to improve prevention, treatment and health outcomes for patients with intracerebral hemorrhage.

The project is an important collaboration between the Brigham and Mass General, the two largest institutions in the Mass General Brigham health care system (formerly known as Partners HealthCare). The Boston-based team of the American Heart Association-Bugher Foundation Center for Excellence in Brain Health after Hemorrhagic Stroke, led by Center Director Jonathan Rosand, will focus on fundamental questions related to brain health and health care disparities. Brain health is defined as the ability to perform all of the activities of cognition, and threats to brain health include cognitive decline, depression and dementia. This work is an important research component of the McCance Center for Brain Health, of which several of the investigators are members.

Correcting Inequities to Enhance Patient Outcomes

Because survivors of intracerebral hemorrhage are at increased risk for progressive deterioration of brain health — and because this deterioration is often accelerated in Blacks and Latinx patients — correcting inequities related to race and ethnicity could considerably enhance long-term patient outcomes. The initiative’s efforts are split into the areas of clinical, basic science and population-based research.

“Hemorrhagic stroke is a disease with marked disparities between white and nonwhite populations,” said Christopher David Anderson, MD, MSc, division chief of stroke and cerebrovascular diseases in the Brigham’s Department of Neurology, who is leading the population-based science effort. “The goal of our project is to improve brain health after hemorrhagic stroke, which will prevent further decline and poor outcomes for patients. We think that immediately after the patient has suffered a stroke is a good time to intervene and put them on a path toward better health.”

Building a Tool to Improve Long-Term Care in Stroke Survivors

The population-based science component of the project is focused on building a tool that will help remind physicians of the importance of ongoing care. Part of the grant will go toward building capabilities into the electronic health record that will pop up alerts and reminders that keep health care providers oriented toward longer-term issues.

“For patients who survive hemorrhagic stroke, we need to think of this time immediately afterward as a teachable moment, where physicians can intervene and provide guidance before sending them back into the community,” Dr. Anderson said. “We can remind physicians that this is a great opportunity to look at other factors that contribute to health, like cholesterol levels and diabetes control.”

He added that two of the biggest risk factors for patients who have had hemorrhagic stroke, especially older people and minorities, are social isolation caused by vision and hearing loss and obstructive sleep apnea.

“We can use this time to consult with patients on these topics and guide them toward resources,” Dr. Anderson said. “We’re using this new award to roll out these tools across all of the Mass General Brigham hospitals to hopefully improve care for everyone.”

The team plans to eventually conduct a clinical trial to evaluate whether use of the tool can lead to better patient outcomes. Another effort within Dr. Anderson’s portion of the project will involve building and testing polygenic risk scores and determining how useful they are for diverse populations.

Collaborating on Projects Related to Blood Pressure and Siderosis

A focus of the clinical portion of the project, led by Alessandro Biffi, MD, director of the Aging and Brain Health Research Group at Mass General, will be the study of social determinants of health and social networks on blood pressure control, which is a risk factor for both cognitive decline and additional intracerebral hemorrhage events.

The project’s basic science component, led by Susanne van Veluw, PhD, also of Mass General, will use human brain tissue and animal models to understand the neuropathology and mechanisms involved in cortical superficial siderosis, a more recently discovered strong risk factor for intracerebral hemorrhage. “There’s a lot of cross-talk between these three projects,” Dr. Anderson said. “The discoveries that we make in each of these areas with regard to risk factors will inform the others.”

Another aspect of Dr. Anderson’s project is being done in collaboration with investigators at Tougaloo College, a historically black institution in Jackson, Mississippi. He has previously worked with the team there on a similar project related to atrial fibrillation.

“This relationship not only gives me the opportunity to provide mentorship to someone who’s interested in medicine and to help train the next generation of investigators, but also to work with investigators who can provide a different perspective,” he concluded. “It’s a big component of the American Heart Association’s overall mission and of what this grant is supposed to accomplish.”

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STUDY FINDS MECHANICAL PROBLEMS OF THE KNEE MORE OFTEN LINKED TO CARTILAGE DAMAGE RATHER THAN MENISCAL PATHOLOGY

Source: Brigham and Women's Hospital
Date: 5/17/2021
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Mechanical problems with the knee, which patients may describe as locking, grinding or clicking, have traditionally been associated with meniscal tears. But a new study from investigators at Brigham and Women’s Hospital has found that these symptoms are more often driven by cartilage damage rather than meniscal pathology.

Findings from the study were published recently in the Journal of Bone and Joint Surgery.

“We’ve always thought that if a patient comes in and says their knee is catching or locking, it must be due to meniscal pathology,” said senior author Elizabeth G. Matzkin, MD, surgical director for women’s musculoskeletal health and chief of women’s sports medicine in the Brigham’s Department of Orthopaedic Surgery. “This research suggests that’s often not the case.”

Prospective Data Aid in Analysis

For the study, the investigators prospectively gathered data on 565 patients who were scheduled to undergo knee arthroscopy between 2012 and 2019. Patient-reported knee symptoms (PRKS) were collected before surgery using the Knee Injury and Osteoarthritis Score Questionnaire.

When the patients later underwent surgery, the investigators were able to examine the specific pathological conditions in the knee. They found that tri-compartmental cartilage damage was associated with significantly worse PRKS. Surprisingly, they didn’t observe an association between meniscal pathology and preoperative PRKS. Most patients with a degenerative meniscal tear, however, had concomitant cartilage pathology.

“These findings question traditional teaching and force us to dig deeper to understand where these symptoms are coming from,” Dr. Matzkin said. “Patients with these mechanical symptoms have always been grouped together, but perhaps they shouldn’t be.”

Linking Surgical Outcomes to Pathology

Dr. Matzkin’s team is now completing the second part of this study, which looks at one- and two-year outcomes after arthroscopy. The study aims to determine how patients do postoperatively, whether they had meniscal pathology, cartilage damage or both. Early findings suggest that outcomes are good regardless of the underlying causes of the symptoms that led the patients to seek out surgery.

Meniscal pathology and cartilage pathology often go hand in hand, especially in people with osteoarthritis, Dr. Matzkin noted. “We know that we’re helping patients with these surgeries,” she concluded. “But this study will help us further investigate how we are helping them.”

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DOUBLE DISCRIMINATION: A CALL TO END PAY AND GENDER DISPARITIES IN GYNECOLOGIC SURGERY

Source: Brigham and Women's Hospital
Date: 5/11/2021
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The disparity in pay between gynecologic surgery and other surgical specialties has been well-established. In a recent commentary, faculty from Brigham and Women’s Hospital and Northwestern University describe the history of this issue and other influences that drive what they call “double discrimination” — lower pay in an area of surgery that has the largest proportion of female surgeons and one that serves primarily female patients.

The authors call for changes that would create equity in reimbursement rates for gynecologic surgery, raising them to the level of other similar surgical specialties. The commentary was published in April 2021 in Obstetrics & Gynecology (download paper here).

“From an anatomical standpoint, we shouldn’t reimburse at lower rates for women’s surgery than for men’s surgery,” said senior author Louise Perkins King, MD, JD, a surgeon in the Brigham’s Division of Minimally Invasive Gynecologic Surgery and a member of the Center for Bioethics at Harvard Medical School. Some of the reasons why this is the case are noted in the commentary.

The Basis for Differences in Reimbursement

The differences in fees are due in large part to the rates at which Medicare and Medicaid reimburse surgeons. In the article, the authors cited two papers — one from 1997 and one from 2017 — that described the differences in the relative value unit assigned to gynecologic procedures compared to urologic procedures. Urologic procedures were used as the comparison because they are most closely related to gynecologic surgeries. Additionally, because a higher proportion of urologic surgeries are performed on men, it allowed the researchers to look at the differences in relation to patients’ biological sex.

They also discussed the 2007 Supreme Court case in which a woman named Lilly Ledbetter sued her former employer, Goodyear Tire and Rubber Company, over gender-based pay discrimination. The late Justice Ruth Bader Ginsburg dissented to the ruling against Ms. Ledbetter’s case, noting the many harms of gender-based pay discrimination. Justice Ginsburg’s legacy compelled the authors to point out this discrimination in medicine and the potential harm for patients.

“The fact that gynecologic surgery doesn’t pay as much as other specialties means that most obstetrician-gynecologists primarily practice obstetrics, which also pays lower than many other subspecialties, but pays a little bit better [than gynecologic surgery],” Dr. King said. “For that reason, many gynecologic surgeons, especially those in private practice, operate infrequently. This, in turn, can lead to higher complication rates, as referenced in literature included in the commentary, because the surgeons don’t have as much experience.”

Creating Equity in Billing and Reimbursement

The paper calls for new legislation that would create equity in billing and reimbursement from Medicare and Medicaid, which Dr. King said would have the trickle-down effect of also increasing reimbursement levels from private insurance companies. She explained that this would allow more gynecologists to focus exclusively on surgery, raising their level of expertise and ultimately leading to better patient outcomes.

Dr. King added that, in an unusual move, the journal published all of the reviewer comments and allowed the authors to respond directly to them.

“I appreciate the journal’s efforts to make the discussions around this topic open and transparent,” Dr. King concluded. “I encourage anyone who is interested to review the many points that we have put forward about why this issue is so important.”

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STUDYING NEW APPROACHES FOR IMMUNOTHERAPY IN RENAL CANCER

Source: Brigham and Women's Hospital
Date: 2/3/2021
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Immunotherapy with checkpoint inhibitor drugs is an emerging treatment for renal cell carcinoma. Now investigators from Brigham and Women’s Hospital have reported the results from lab research looking at a potential new way to boost the immune system’s ability to fight cancer.

The approach, which uses a small molecule to target the protease inhibitor SerpinB9, not only affects tumor cells themselves but also cells in the microenvironment, including immunosuppressive cells. Results from this work were published recently in Cell.

“Not much is known about this protein and its role in tumor immunity, so more work needs to be done,” said Reza Abdi, MD, of the Brigham’s Division of Renal Medicine and the paper’s senior author. “But based on our early work, we thought that targeting SerpinB9 would introduce a potentially more multifaceted approach than current checkpoint inhibitor drugs.”

Targeting a Molecule That Protects Cells From Attack

SerpinB9 is an inhibitor of granzyme B, a protease that induces apoptosis. Granzyme B is commonly found in two types of immune cells, natural killer cells and cytotoxic T cells, and they use it to attack tumor cells. The role of SerpinB9 is to prevent granzyme B from attacking the immune cells themselves.

“It appears, however, that tumor cells put out their own SerpinB9 to fight against immune cells,” Dr. Abdi said. “That makes this protease inhibitor a potential target for anticancer therapy.”

In the paper, the investigators report that when they used a small molecule to block SerpinB9, it slowed the growth of tumor cells, indicating this molecule is important for tumor growth. The research was done in cell cultures and in mouse models of several types of cancer, including renal cancer. Additionally, targeted SerpinB9 appeared to affect both the tumor stromal cells and immunosuppressive cells in the tumor.

Looking for Synergistic Effects and Future Applications

Dr. Abdi said that one focus of his current work is optimizing the molecules that could be used to target SerpinB9. Additional research is needed on the binding and kinetics as well as on potential toxicities. He explained that because SerpinB9 can be blocked with a small molecule rather than an antibody, this type of drug may prove less costly to develop.

“Checkpoint inhibitors can have frequent and sometimes lethal toxicities,” he noted. “This should prompt us to look for other approaches and compare them head to head for both efficacy and toxicity.”

Dr. Abdi also plans to study in more depth whether adding a SerpinB9-targeting drug to treatment with an immune checkpoint inhibitor could have a synergistic effect. “Immune checkpoint drugs don’t work very well on ‘cold’ tumors that lack immune infiltration,” he said. “Because SerpinB9 is also found in the tumor microenvironment, blocking it may make these drugs work better.”

In addition to its potential applications for renal cancer, this drug could prove effective in other solid tumors as well. The paper also studied it in models of melanoma, breast cancer and lung cancer. “This is an exciting field, and the ability to target a different mechanism of action in cancer opens up new opportunities for treatment,” Dr. Abdi concluded.

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FOCUSING ON OUTCOMES OF TREATMENT FOR SHOULDER INSTABILITY

Source: Brigham and Women's Hospital
Date: 1/25/2021
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Shoulder instability is a relatively common concern in athletes, especially among those who play contact sports such as football, basketball and rugby. This condition has a number of treatment options, including physical therapy and various surgical procedures, but much remains unclear about how to determine the best course for each patient.

One initiative that aims to address these questions is the Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Group. The group’s shoulder instability study is co-led by Carolyn M. Hettrich, MD, MPH, chief of the shoulder service in the Department of Orthopaedic Surgery at Brigham and Women’s Hospital.

“This study is aimed at looking at predictors of outcomes for patients who undergo surgery for shoulder instability,” Dr. Hettrich said. “It is through understanding what leads to both excellent and poor outcomes that we can improve patient care.”

So far, more than 1,800 patients have been enrolled in the study, and 16 papers using data from the project already have been published. The investigators will continue to follow study participants for up to a decade after their surgeries to determine long-term outcomes, including the predictors of arthritis.

MOON Shoulder Group Studies

The MOON Shoulder Group is the largest prospective cohort of patients with shoulder problems in the world. Dr. Hettrich launched the group’s shoulder instability study with Brian Wolf, MD, in 2012, when she was at the University of Iowa. The study now includes 26 surgeons from across the country. In addition to studying shoulder instability, the larger group also has studies looking at rotator cuff tears and shoulder arthroplasty.

“These efforts have already produced important findings,” Dr. Hettrich said. “We have published research looking at differences in age, gender and race among patients. We’ve also looked at return-to-play in athletes.”

As part of the study, data are being collected on all patients at the time of surgery and at several points of follow-up: six months, two years, six years and 10 years. All surgeries for shoulder instability, both open and arthroscopic, are included in the study.

“Based on what we’ve already learned, we know that we should consider surgery for shoulder instability much earlier in certain groups of patients,” Dr. Hettrich said. “This is in part because subsequent dislocations can predispose people toward having more loss of cartilage and bone, which can increase the risk of repeat dislocation and poor outcomes.”

Using Data to Optimize Patient Outcomes

One recent study from Dr. Hettrich, presented at the virtual meeting of the American Shoulder and Elbow Surgeons in October, looked at the predictors of bone loss at the time of surgery. The prospective, multicenter study, which included 895 patients, found that an increased number of preoperative shoulder dislocations was the strongest modifiable predictor of glenoid and humeral bone loss, which is known to result in worse outcomes. It was one of only eight studies selected for presentation at the meeting. A poster featuring details of this same study was also awarded as the top poster in the category of Shoulder and Elbow by the American Orthopaedic Association and will be featured at this year’s Annual Leadership Meetings.

Dr. Hettrich said her group plans to submit the study for publication. They will also be publishing an online calculator for predictors of bone loss that orthopaedic surgeons and their patients can use when making treatment decisions.

“The Brigham is one of the lead sites for the shoulder instability study,” Dr. Hettrich concluded. “We’re on the forefront of looking at what allows patients to do well and what may cause them to do poorly, and then applying this information to the care of our patients so that we can optimize their outcomes.”

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IMPROVING TELEHEALTH IN PSYCHIATRY FOR NON-ENGLISH SPEAKERS

Source: Brigham and Women's Hospital
Date: 1/7/2021
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Telemedicine has become an increasingly important mode of care during the COVID-19 pandemic. Certain specialties lend themselves to telemedicine to a greater degree than others. One of these is psychiatry, thanks in large part to relevance of observation and conversation with patients and their families to obtain neuropsychiatric history.

However, certain populations of patients have a more difficult time accepting telemedicine than others — for instance, those who are over age 60 or don’t speak English. For those people who are in both of these categories, experts at Brigham and Women’s Hospital are conducting research to identify specific barriers to care and soliciting feedback on how the needs of these vulnerable patients can be better addressed.

“The language barrier alone is a big issue,” said Juan Carlos Urizar, MD, director of clinical services in the Brigham’s Division of Geriatric Psychiatry and a neuropsychiatrist specializing in treating patients who have psychiatric disorders related to neurological conditions. “But we also want to understand the other underlying factors that may make it difficult for us to reach these patients.”

Identifying Barriers to Telemedicine in Psychiatry

According to Dr. Urizar, a significant portion of patients seen within his division, both at the main hospital and at the Brigham’s satellite clinics, are Hispanic. Many of them don’t speak English, necessitating either health care providers who speak Spanish or interpreters.

“When the pandemic surged during the spring and summer of 2020, we were not able to connect as efficiently with our Hispanic patients,” he said. “We learned that in many cases, it was more than language barriers.”

One common problem was the lack of technology, such as computers, tablets and smartphones. But even people who have access to these technologies and use them to communicate with family members may feel uncomfortable with the specific software and platforms that are required for telemedicine due to privacy requirements, Dr. Urizar noted. Other concerns that have come up in this patient population are issues of racial discrimination as well as fears that sessions could be recorded and used against them in the context of deportation.

Reaching a Population That Can Benefit From Telehealth

Dr. Urizar and his colleagues, including geriatric psychiatrist Catherine Gonzalez, MD, and medical interpreter Margarita Avila-Urizar, MD, are now embarking on research to survey their patients and get to the heart of these dynamics.

“It’s important for us to understand these issues. We know that video calls are important in evaluating many of our patients, in large part because they most closely resemble face-to-face meetings,” Dr. Urizar explained. Because he often treats patients with neurological disorders such as Parkinson’s disease and Alzheimer’s disease, it is crucial for him to be able to see and hear his patients.

Dr. Urizar explained that even after the COVID-19 pandemic is over, telemedicine will continue to be an important part of medical care, especially in neuropsychiatry. “Many of my patients have problems getting to their appointments because of limitations with their mobility and other issues,” he said. “For these populations, telemedicine will continue to be a good way to reach out and connect.”

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EMPHASIZING PREVENTION IN ALZHEIMER’S DISEASE TRIALS

Source: Brigham and Women's Hospital
Date: 1/21/2021
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For most chronic diseases, improvements in care over the past few decades have resulted from early interventions that prevent disease progression. Brigham and Women’s Hospital investigators, along with collaborators at other institutions around the world, are applying a similar approach to the early detection and prevention of Alzheimer’s disease (AD).

Some of this research is being conducted through the Davis Alzheimer Prevention Program (APP), launched in July 2020. Brigham neurologists Reisa A. Sperling, MD, MMSc, and Dennis J. Selkoe, MD, are co-leading the program.

“The overall goal of the Davis APP is to accelerate finding a successful preventative treatment for AD,” said Dr. Sperling, an internationally recognized expert in AD and director of the Brigham’s Center for Alzheimer Research and Treatment. “To help reach this goal, we want to select drugs for clinical trials that are more likely to work, as well as more quickly eliminate those that don’t. We also aim to develop more sensitive ways to detect changes in the brain — both with biomarkers in the blood and imaging methods.”

She added that in addition to accelerating work in both of these areas, another important initiative under the Davis APP is to increase the diversity of patients in AD clinical trials. This includes a focus on outreach and community partnerships.

Launching Innovative AD Clinical Trials

Dr. Sperling also serves as principal investigator for the National Institutes of Health-funded Alzheimer’s Clinical Trials Consortium (ACTC), a network of 35 sites across the country focused on finding new ways to prevent and treat AD.

Two trials recently launched under the ACTC are AHEAD 3 and AHEAD 45. Both are investigating the effectiveness of the antibody drug BAN2401 (lecanemab) to slow or stop the accumulation of ß-amyloid in individuals who are at greatest risk of developing AD. The risks are determined by age, family history and PET scans of the brain.

“The AHEAD studies are some of the first to use targeted dosing, where we screen people who are cognitively normal and assign them to a trial based on the amount of ß-amyloid seen on their PET scan,” Dr. Sperling said. “This is a way of offering more personalized medicine.”

In the AHEAD 3 study, patients with low levels of ß-amyloid get monthly dosing of the drug. The AHEAD 45 study includes people with higher levels of ß-amyloid, even though their cognitive function is normal. “With this group, we want to be more aggressive in trying to knock their ß-levels down,” Dr. Sperling said. These trial participants get doses every two weeks for the first two years, then a monthly maintenance dose.

The AHEAD trials were launched last summer in the United States, funded as a public-private partnership with the National Institutes of Health. The AHEAD Study opened its first site in Japan this fall, and up to 100 sites around the world will participate in the coming years.

Different Approaches to Drug Development

As a neurologist who treats AD patients in all levels of cognitive decline, Dr. Sperling recognizes the need to develop better treatments for active disease and preventative drugs. She also has witnessed AD in her own family, with her father and grandfather.

“For people who already have clinical symptoms of Alzheimer’s, I think we will need to do something more aggressive,” she noted. “That will likely be a combination of drugs that target ß-amyloid and drugs that target tau.”

Dr. Sperling stressed the importance of good trial design for some of these combination approaches. “We are now working on how to combine anti-amyloid antibodies with anti-tau drugs and how to measure potential synergistic effects with tau PET imaging,” she said.

Better Screening Methods Support Clinical Trials

Developing and evaluating new interventions to prevent AD progression as well as new treatments to alleviate AD symptoms will require better assays to predict cognitive decline. In a recent study published in Nature Communications, Dr. Sperling co-led a team that looked at a blood test that measures levels of N-terminal fragment of tau (NT1, a protein secreted by neurons in response to ß-amyloid pathology). The test was evaluated in participants in the Harvard Aging Brain Study, a group of cognitively normal older adults who are being followed over time.

The study analyzed the predictive value of NT1 in 236 study participants who were cognitively normal and followed them for an average of five years. The researchers found that participants whose blood samples had higher levels of NT1 at the beginning of the testing period had a higher risk of advancing to mild cognitive impairment. Imaging showed that higher levels of NT1 were also associated with more ß-amyloid plaques and greater accumulation of tau tangles.

“We don’t know yet how dynamic levels of NT1 are in the blood over time, but we know that NT1 goes up pretty early before people have cognitive symptoms,” Dr. Sperling said. “We have high hopes that this may work as an indicator of whether drugs are working, as we move into more prevention trials.”

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STUDYING PANDEMIC’S EFFECT ON MENTAL HEALTH IN YOUNG ADULTS

Source: Brigham and Women's Hospital
Date: 1/7/2021
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The COVID-19 pandemic has been challenging for almost everyone, and different populations have been hit in different ways. For people aged 18–30 years, it has had an outsized effect on mental health, especially in terms of depression, anxiety and post-traumatic stress disorder (PTSD).

“Even before the pandemic, young adults had high rates of mental health problems,” said Cindy H. Liu, PhD, a psychologist in the Department of Pediatric Newborn Medicine and the Department of Psychiatry at Brigham and Women’s Hospital and a Tynan Faculty Research Fellow within the Connors Center for Women’s Health and Gender Biology. “The pandemic hasn’t necessarily caused these problems, but it has exacerbated them.”

She explained that young adults have higher rates of certain mental health conditions because so many are going through a period of extreme change in their lives. “They may be moving away from home for the first time, or graduating or finding their first job,” she said. “They may also be looking for a life partner or thinking about starting families. It’s a time of many transitions.”

Collecting Mental Health Data on Young Adults

Dr. Liu and her colleague Hyeouk Chris Hahm, PhD, of Boston University, have published several articles on mental health in the young-adult population since the onset of the pandemic. One study looked at factors associated with depression, anxiety and PTSD in young adults; one looked at the effects on sleep; and another focused on college students.

“When the pandemic began, college students were one of the first populations who were confronted with disruption,” she noted. “Unlike other groups in the U.S., many of them had to physically move as campuses closed.”

In a viewpoint article published in the Journal of American College Health, Dr. Liu and her coauthors highlighted two urgent priorities for addressing current college mental health needs: the development of strategies for ensuring access to mental health services and intentional outreach to college students with special circumstances. “Such widescale disruptions can do the most damage to those who already face challenges in obtaining resources, even for institutions that actively promote equitable access,” she said.

Two of her other studies employed data collected from a population of 898 young adults who volunteered to be assessed online between April 13, 2020, and May 19, 2020. “We really wanted to document what was transpiring after the United States designated COVID-19 as a pandemic,” she said.

A study published in Psychiatry Research found high levels of depression (43.3%), anxiety (45.4%) and PTSD symptoms (31.8%) in young adults. Participants also reported high levels of loneliness and COVID-19-specific worry along with low tolerance for distress. Another study, also published in Psychiatry Research, looked at the effects of the pandemic specifically on sleep disturbances. “There’s a strong association between mental health and sleep, and it affects quality of life,” she said.

Expanding Mental Health Research Beyond the Pandemic

Since the initial data were collected, the United States has continued to undergo upheaval, in particular in areas surrounding racial discrimination and social justice. Dr. Liu and her colleagues are studying the volunteers from their earlier work to measure further the impact of these circumstances on mental health.

“We know that young adults are quite involved and participating in a lot of the conversations and the advocacy around social justice,” she said. “We didn’t want to discount that.”

Dr. Liu added that because the population of young adults in the United States is more diverse, they are also more likely to be personally affected by racial discrimination. Some of her future work will focus on this issue.

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SOME OBESITY-LINKED DISEASES MAY BE RELATED TO CHOLESTEROL

Source: Brigham and Women's Hospital
Date: 1/25/2021
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Obesity is linked to an increased risk of many diseases, but much remains unknown about the molecular mechanisms underlying this connection. In a new study from Brigham and Women’s Hospital and Harvard Medical School, investigators have found an unexpected role for cholesterol and its effects on the immune system in driving some of these obesity-linked diseases — in particular, with conditions characterized by autoimmunity.

The association turns out to be mediated by interleukin-17 (IL-17), a cytokine that provides important protection against infections. When produced in excess, however, IL-17 is associated with autoimmune-related diseases including psoriasis, rheumatoid arthritis and multiple sclerosis.

“We know that IL-17 is linked with these diseases, and we know that IL-17 is increased in people who are obese,” said Brigham immunologist Lydia Lynch, PhD, senior author of the study published in Nature Immunology. “But the connection to cholesterol was surprising, because these diseases are not typically associated with high cholesterol.”

Discovering Unexpected Links

Dr. Lynch’s lab studies the effects of obesity and diet on the functions of immune cells. Her previous work found that obesity doesn’t affect every type of immune cell in the same way. “It’s not that obesity impairs all immune cells,” she said. “Instead, it skews them toward being IL-17 producers and therefore less cytotoxic, as it impairs natural killer cells and other cells that are associated with recognizing and fighting infections and cancer.”

In the current work, the researchers found the cells that produce high levels of IL-17 have lipid droplets inside of them, which is not typical of immune cells. Furthermore, mice that were fed a high-fat diet had higher IL-17 production. Alternatively, levels of IL-17 could be reduced by blocking lipid uptake in the mice.

When the team took a closer look at the type of lipids inside the cells, they discovered that in addition to triglycerides and fatty acids, which were expected, the cells contained cholesterol droplets. “It appeared that cholesterol was particularly associated with these IL-17-producing cells, suggesting a possible link between high cholesterol and IL-17-related diseases like psoriasis,” Dr. Lynch explained.

Combination of Obesity and Type 2 Diabetes Increases Risks

Dr. Lynch pointed out that one important aspect to note about the connections between obesity and disease is that the effects of obesity on the immune system are not the same in every individual. Other factors are involved as well.

For example, people who have obesity but do not have type 2 diabetes or other hallmarks of metabolic syndrome do not necessarily carry the same risks as those who have obesity and metabolic syndrome. Their immune system is less affected by obesity.

“It’s not just obesity on its own that affects disease risk, and it’s not just type 2 diabetes on its own either,” she said. “It’s the combination of obesity and type 2 diabetes that seems to have the worst effect on the immune system.”

Implications for Future Research

Although cholesterol appears to be associated with increased IL-17, the approach of treating high cholesterol to lower disease risk may not be so straightforward.

“We know that weight loss is associated with reduced IL-17, so lowering cholesterol through diet is probably beneficial,” Dr. Lynch said. “However, our early work has suggested that it may not be that simple. That’s because lowering cholesterol seems to cause these cells to start making their own lipids and cholesterol if they can’t take them up from the environment.”

She added, however, that much more work is needed before this connection can be fully understood.

Findings from this research have implications beyond autoimmune disorders. Previous work in Dr. Lynch’s lab focused on the role of the immune system in relation to obesity and cancer — specifically, how the cellular environment in people with obesity impairs immunosurveillance. This earlier research, which has suggested that metabolic reprogramming of natural killer cells may improve cancer outcomes in people with obesity, also has implications for immunosurveillance more broadly, including the connections between obesity and infectious diseases like COVID-19.

Research like Dr. Lynch’s is also helping to fuel treatment at the Brigham’s Center for Weight Management and Wellness, which offers medical, endoscopic and surgical weight management services and interventions. Caroline Apovian, MD, co-director of the center and a physician within the Brigham’s Division of Endocrinology, Diabetes and Hypertension says that research like this is instrumental in helping to understand what mechanisms cause patients with obesity to develop certain diseases.

“The more we understand about the triggers for certain obesity-linked disease’s, the better equipped we are to help our patients and adapt our treatment approaches.”