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Guidelines on Perimenopausal Depression Recognize Vulnerable Time in Women’s Lives

Source: Brigham and Women's Hospital - On a Mission
Date: 02/07/2019
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Perimenopausal mood changes and depression are experienced in some form by about one-fourth of women undergoing the transition to menopause. Yet until recently, there was no formal direction for healthcare providers in identifying and treating this condition. That changed in September 2018, when a panel led by the National Network of Depression Centers with the support of the North American Menopause Society published the first-ever guidelines.

“The three main hormonally linked mood conditions in women are postpartum depression (PPD), premenstrual syndrome (PMS) and perimenopausal depression,” said Hadine Joffe, MD, MSc, a psychiatrist and executive director of the Connors Center for Women’s Health and Gender Biology and vice chair of psychiatry research in the Department of Psychiatry at Brigham and Women’s Hospital. Dr. Joffe also served on the task force that developed the new guidelines. “PPD and PMS have been well-studied, but much less is known about perimenopausal depression than the other two,” she added. “Until now, there hasn’t been any guidance for clinicians in recognizing this as a vulnerable period in a woman’s life.”

Dr. Joffe explained that one reason for difficulty in identifying perimenopausal depression is that the period of risk usually stretches over several years and may not be immediately recognized, in comparison to a regular, cyclical event such as PMS or the distinct experience of giving birth. “Perimenopause is more nebulous,” said Dr. Joffe, who also is director of the Women’s Hormone and Aging Research Program. “Perimenopause lasts on average about four years. It’s hard to be able to pinpoint depression that arises during this time and say, ‘Aha, this is definitely hormonally linked.’”

Dr. Joffe’s research focuses on whether perimenopausal depression is a result of changes in reproductive hormones and/or common menopause symptoms such as hot flashes and insomnia. She also studies how to treat menopause-related symptoms, including the efficacy of hormonal and nonhormonal interventions for this constellation of symptoms. Last year, she co-authored the JAMA Psychiatry editorial, Should Hormone Therapy Be Used to Prevent Depressive Symptoms During the Menopause Transition?

The new guidelines for perimenopausal depression aim to help by providing information for healthcare providers. They focused on five main areas:

  • Epidemiology of depressive symptoms and depressive disorders
  • Clinical presentation of depression
  • Therapeutic effects of antidepressant medications
  • Effects of hormone therapy
  • Efficacy of other therapies, such as psychotherapy, exercise and natural health products

As members of the Brigham’s Women’s Mental Health Division, Dr. Joffe and colleagues focus on addressing the needs of women with depression and other mental health problems related to pregnancy, postpartum, PMS, perimenopause and other hormonal changes. These guidelines will be incorporated into their clinical practices and their teaching of medical students and psychiatry residents, many of whom are interested in women’s mental health and seek this expert knowledge for their future practices.

This Brigham team also trains others through a one-year dedicated Women’s Mental Health Fellowship. Working with Dr. Joffe, trainees are taught to recognize and treat perimenopausal depression. This training is part of a unique fellowship that provides highly expert and comprehensive training across the field of women’s mental health. Dr. Joffe also lectures on the topic at national meetings and local continuing medical education courses.

The most common symptoms of perimenopause are hot flashes and sleeping difficulties — not depression. But Dr. Joffe’s research has shown that women who experience the former issues are more susceptible to developing mild symptoms of depression, especially because lack of sleep can contribute to mood disorders.

Most women with mood changes during perimenopause have milder symptoms that do not constitute a full-blown mood disorder episode. However, a smaller group develops major depression during perimenopause. Those women generally have a history of depression, Dr. Joffe said. For these women, she added, it’s important to recognize perimenopause as a period of vulnerability for recurrence. Furthermore, physicians who treat these patients should monitor them more closely during perimenopause and should be careful about withdrawing treatment when women may be more vulnerable.

Dr. Joffe emphasized another important reason for creating guidelines: offering relief for those who are suffering. “The good news is that this condition is hugely treatable, once we recognize that it’s happening. It’s also important to recognize that this is a limited period of vulnerability and that the need for treatment passes once the woman passes through menopause and all the hormone changes settle down in postmenopause.”

For mild depression that is related to the hot flashes and sleep problems caused by hormone fluctuations, the task force noted that hormone therapy may be a beneficial approach for many women, particularly those with concomitant vasomotor symptoms, although estrogen therapy is not approved for this use. “If the depression is more severe or a recurrence of an earlier incident of depression,” Dr. Joffe concluded, “the best treatment is likely to be more traditional approaches, such as antidepressants and psychotherapy.”

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Maximizing Function in Full Face Transplant Recipients

Source: Brigham and Women's Hospital - On a Mission
Date: 12/12/2019
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In 2011, Brigham and Women’s Hospital made headlines as the site of the nation’s first full face transplant. In July 2019, the Brigham set another milestone with the world’s first full face transplant procedure on a black patient and the oldest recipient ever. It was the ninth face transplant at the Brigham and the 15th nationwide.

Robert Chelsea, a 68-year-old man from California, came to the Brigham with disfiguring facial injuries resulting from a traumatic, fiery car crash six years earlier. After the accident, Chelsea went through over 30 surgeries, yet his face remained severely scarred. His lips, part of his nose and part of his left ear couldn’t be reconstructed, limiting his ability to eat, drink, smile and speak normally.

Donald J. Annino, MD, DMD, from the Division of Otolaryngology-Head and Neck Surgery, was among those responsible for attaching the donor face to Chelsea and making sure he regained optimum function after the procedure. His surgical expertise related to the microvascular and facial nervous systems made him a key part of the surgical team.

“Otolaryngology expertise is crucial to helping face transplant recipients resume breathing, swallowing and speaking function,” Dr. Annino explained. “We focus on how and what the patient is eating, how they are breathing, how their tongue functions and how well they can communicate both before and after the procedure. We also closely evaluate the facial nerves to determine the specific nerve branches that need to be harvested from the donor face in order to achieve that optimum function.”

Dr. Annino worked closely with the surgical lead, Bohdan Pomahac, MD, the Roberta and Stephen R. Weiner Distinguished Chair in Surgery and director of plastic surgery transplantation.

“Our experience has demonstrated that face transplantation is a viable option for patients with severe disfigurement and limited function who have no alternatives,” Dr. Pomahac said. “We recently published a follow-up study of the first patients to receive a face transplant at the Brigham, which showed they had a robust return of facial motor and sensory functions, allowing them to socially reintegrate in a way that would not have been possible pre-transplant.”

Face transplantation is not a first-line treatment and is never considered for strictly aesthetic reasons. To be a candidate, a patient must have severe functional limitations, sometimes following many rounds of conventional reconstruction procedures. Patients must be willing to go through extensive psychological counseling both pre- and post-procedure. In addition, because transplantation requires the patient’s immune system to be suppressed for the rest of their life to keep their bodies from rejecting the donor organ, patients must demonstrate a history of good compliance with medication protocols and other therapies.

Chelsea met the requirements. After an evaluation by the surgical team and an extensive screening process, he began the wait for a donor, a process that took longer than for previous Brigham face transplants due to his skin tone.

“Face transplantation has significant obstacles that don’t exist with transplanting other organs such as livers, lungs and kidneys,” said Dr. Annino. “The donor and the recipient need to be a good match in terms of gender, age and skin tone. Complexion shade can be especially hard to match, even between two African Americans, because the range of skin tones is much larger than with whites.”

Due to the intricacies of blending skin of different shades of the donor’s face with Chelsea’s native one, the decision was made to pursue full face transplant. Once a donor of the same gender, a similar age and a nearly identical skin color became available, the Brigham sprang into action. More than 45 physicians, nurses, anesthesiologists, residents and research fellows assisted during the 16-hour transplantation procedure.

After the surgery, Chelsea began the recovery process. For nearly a month, he remained in the hospital, monitored closely by Brigham transplant medicine and infectious disease physicians for signs of rejection. Under the direction of Dr. Annino, occupational therapists helped him regain the ability to swallow after his tracheotomy and feeding tubes were removed.

“One of our goals was to make sure he was able to ingest proper nutrition while also protecting his airway,” said Dr. Annino.

Upon leaving the hospital, Chelsea convalesced nearby, continuing therapy and starting a lifelong immune-suppression medication protocol crucial to preventing infection.

“Our social workers found a temporary apartment in Boston, and a couple of his family members came to help with his follow-up care,” Dr. Annino said. “His recovery went very well, and he was able to return home to California two-and-a-half months after surgery.”

According to Dr. Annino, Chelsea is not the first face transplant patient to come to the Brigham from outside of Massachusetts. Eight of the Brigham’s nine face transplant recipients have hailed from other regions of the country.

“The foundation of the Brigham’s leadership reputation in face transplants is strong,” he concluded. “We have a well-established transplant center with an extensive history of transplants in general, along with the institutional knowledge, specialized surgeons and multidisciplinary teams needed to achieve good results. When people have a choice, they choose Brigham and Women’s Hospital.”

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Using MRI to Decode the Brain’s Inner Workings

Source: Brigham and Women's Hospital - On a Mission
Date: 11/12/2019
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Thanks to imaging technologies like CT, MRI and PET, researchers who study the brain are able to peer inside its “black box” to learn how different parts of the brain interact and how those interactions change in response to disease or injury.

The Psychiatry Neuroimaging Laboratory at Brigham and Women’s Hospital, directed by Martha E. Shenton, PhD, was established to understand more about brain abnormalities and their role in neuropsychiatric disorders. The lab makes use of state-of-the-art neuroimaging techniques.

“From the beginning, my research has been focused on developing and refining new technology to study schizophrenia and traumatic brain injury [TBI] in living brains,” said Dr. Shenton, who founded the laboratory in 2005. “We are excited to be taking this research into the clinic.”

Visualizing Brain Changes Across the Lifespan

Much of Dr. Shenton’s work has concentrated on MRI. Unlike types of imaging that provide far less detail, MRI enables researchers to distinguish between the gray matter (which contains the cell bodies, dendrites and axon terminals of neurons, as well as the synapses) and the white matter (which is made of the axons that connect different areas of gray matter to each other). They can also use it to analyze the flow of fluid between different parts of the brain.

One of the major goals of the laboratory is to build an atlas of what normal brains look like across the entire human lifespan. This will enable both researchers and clinicians to better understand changes over time and changes in response to damage.

“When you test someone’s cholesterol levels in the blood, you need to know the normative range to test it against,” Dr. Shenton explained. “It’s the same with brain scans. If you are looking at someone who is 30 years old and has a concussion, you want to know what to expect in a healthy brain that’s been matched for age, gender and other factors. That gives you a better understanding of how severe the injury is and how it may be affecting brain function.”

Improved Predictive Modeling

Dr. Shenton believes the tools she’s developing will eventually lead to better diagnostic and predictive models for schizophrenia and other neurological disorders. “By identifying individuals who are at high risk for developing schizophrenia and studying them over time, we can determine how measures like inflammation in the brain may affect the onset and progression of the disease as well as how it responds to therapy,” she said.

She added that this research may lead to better clinical trials for schizophrenia by enabling better classification of patients by the particular features of their disease. “Schizophrenia is a very heterogeneous disease, and not everyone is going to respond to the same drug in the same way,” she said. “If we can figure out how to group people into smaller, more homogeneous groups based on the characteristics of their disease, we’ll be able to match them better to the right clinical trial.”

Dr. Shenton is also participating in research on TBI and chronic traumatic encephalopathy (CTE) funded in part by the National Institute of Neurological Diseases and Stroke. She along with other researchers on the team are looking at levels of tau and amyloid-beta proteins in the brain to understand how changes here may lead to complications later in life, as CTE is currently a diagnosis only at post-mortem. Being able to track brain changes over time will thus provide more information that may assist in detecting those most vulnerable to CTE and other neurodegenerative diseases.

“We hope to eventually collect enough data to help football players understand their risk for future brain complications,” she concluded.

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Neuropsychiatry Focuses on Bringing Two Fields Together

Source: Brigham and Women's Hospital - On a Mission
Date: 11/12/2019
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It’s not uncommon for people who have neurological disorders to experience behavioral and emotional symptoms. The field of neuropsychiatry is dedicated to addressing this issue and bringing a neurobiological understanding to the field of psychiatry.

“We focus on the intersection between neurology and psychiatry and on understanding the full range of cognitive, emotional and behavioral manifestations that can present with different neurological disorders,” said Gaston C. Baslet, MD, chief of the Neuropsychiatry Division in the Brigham and Women’s Hospital Department of Psychiatry and co-director of the Center for Brain/Mind Medicine. “There’s a lot of overlap, and it’s important for these two specialties to work together to understand the emotional disorders that can arise from alterations in the function of the brain.”

At the Intersection of Psychiatry and Neurology

Psychiatric conditions are common in people with neurological diseases, including Alzheimer’s disease and other forms of dementia, multiple sclerosis and epilepsy. They also can occur in people with brain tumors and those who have experienced traumatic brain injuries, strokes or infectious diseases of the nervous system, among other conditions. “We want to understand how a brain affected by neurological illness can also have all sorts of impact on emotional and cognitive function,” Dr. Baslet said.

“The Brigham has a large group of professionals interested in brain and behavior. This puts us in a unique position to better understand and offer help to address these disorders,” he added. “We have a number of experts in neuropsychiatry in our group. Additionally, as part of the Center for Brain/Mind Medicine, we work closely and collaborate with the behavioral neurology group and the neuropsychology group.”

As a tertiary care center, the Brigham sees people with both common and rare neurologic and psychiatric disorders. Because of the large volume of inpatients who are in more acute stages of neurological disease—which frequently has a psychiatric component—inpatient consultations are also a growing area of specialization.

Clinical research is an important element of the work done by the Brigham’s neuropsychiatrists. “We are really expanding our research as a way to grow our division,” Dr. Baslet said. “We are developing clinical trials that are at the cutting edge of research to try to better treat functional neurological disorders.” He is particularly excited about one trial that is looking at the role of inflammation in severe depression and targeting that inflammation as a treatment strategy.

The Future of Neuropsychiatry

Training the next generation of leaders in the field is another key component of the Brigham’s neuropsychiatry program. The Fellowship in Behavioral Neurology/Neuropsychiatry is available to those who have completed residencies in either neurology or psychiatry. It allows trainees to gain experience in both behavioral neurology, which focuses on cognitive impairment, and neuropsychiatry, which focuses on psychiatric and emotional disorders arising from neurological disease. Fellows spend two years learning to diagnose and treat a broad range of neuropsychiatric disorders. They also have the opportunity to pursue various areas of research.

Through Harvard Medical School, the Brigham is also involved in continuing medical education classes for those who are already practicing medicine and want a greater understanding of the depth and breadth of neuropsychiatry.

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Novel Initiatives Address Complexities in Treating Rheumatic Diseases

Source: Brigham and Women's Hospital - On a Mission
Date: 12/04/2019
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There are many challenges to treating autoimmune diseases such as rheumatoid arthritis and lupus. Brigham and Women’s Hospital has recently undertaken a number of new initiatives to address some of these challenges and improve patient care.

“One of the biggest problems we see is lack of access, especially for more specialized rheumatology services,” said Susan Ritter, MD, PhD, associate medical director of the Brigham and Women’s Arthritis Center. “This is a larger issue in other parts of the country, where there are not enough providers to meet the needs of the population. However, it’s a problem even in Boston. We have a large number of providers, but there is so much demand.”

One project that the Brigham has undertaken to address this concern involves optimizing best practices for recurring functions in patient care. Through a pilot program, members of the rheumatology team—including physicians, nurses and medical assistants—took a closer look at common questions and requests from patients and identified ways to establish and enhance processes for meeting these needs.

“We focused on ways to improve best practices for 20 of the most common things that we do on a regular basis,” Dr. Ritter said. “For example: What do we do when a patient calls and has a question about medication? How do we optimize referrals for lab tests? We’ve created documentation to streamline all of these frequently occurring processes.”

Meeting Demands Through Education and Prioritization

Continuing medical education programs for primary care providers that focus on rheumatic diseases, offered through Harvard Medical School, are another important way the Brigham is meeting increasing demands in patient care. Patients stand to benefit significantly when primary care providers are educated on the initial steps needed for evaluation and management of these diseases as well as on the signs and symptoms that should prompt more urgent referrals to rheumatology specialists.

In diseases for which it’s vital for patients to see a specialist right away, the team at the Brigham has put systems in place to ensure those with more urgent needs are prioritized. “One example of this is giant cell arteritis, where it’s important that we get a biopsy within two weeks,” Dr. Ritter explained. “We’ve created a button right in our computer system that flags these patients in our system. It allows us to fast-track their care.”

Another recurring challenge is getting buy-in from insurance companies to approve some of the newer small molecule and biologic therapies. This is a particular concern in the treatment of rheumatoid arthritis because a number of medications are now available, but these drugs are expensive. When patients can benefit, however, it’s important that they start taking these medications as soon as possible to prevent the permanent damage to joints that can result from unresolved inflammation.

“When patients check in for their appointments, we give them iPads and they’re asked a series of questions about their medications and symptoms,” Dr. Ritter said. “We can use that data to show over time how well somebody is responding to a particular therapy. These data allow us to identify when the therapy isn’t working, so we know that we should try something different. All of this goes right into our electronic medical records and is also available within the clinic documentation.”

Dr. Ritter noted that this system has the added benefit of helping patients become more active in their own care by allowing them to see trends in their data. “We will be moving toward doing this for other rheumatic diseases,” she said. “It helps us to better care for our patients and to justify to the insurance companies the therapies that they need.”

High Volume Leads to Specialized Expertise

Because of the high volume of patients seen at the Brigham, individual rheumatologists can develop special areas of expertise in conditions that are not commonly seen at other centers. One emerging specialization is in immune-related adverse events caused by checkpoint inhibitors for cancer.

“We have several doctors who are specifically interested in seeing these patients,” Dr. Ritter said. “We work with the oncologists at the Dana-Farber Cancer Institute to make sure patients are seen quickly.” The goal of this collaboration is to optimize cancer care while managing the many immune-related adverse events from these drugs.

Another example of a team approach is in the treatment of Raynaud’s disease. A specialized clinic allows patients to see experts in rheumatology and cardiovascular disease on the same day. In addition, it enables physicians to collaborate and communicate with each other on treatment methods.

The Brigham also has experts with an interest in working with people who have lupus. “As part of our Lupus Center, we provide additional information to patients in the form of regular newsletters as well as other services,” Dr. Ritter said. “The health care system can be a challenge for people with lupus, many of whom come from disadvantaged backgrounds. We want to help them get the care they need.”

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Research Adds to Arsenal of Treatments for Rheumatoid Arthritis

Source: Brigham and Women's Hospital - On a Mission
Date: 12/04/2019
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Beginning with methotrexate in the mid-1980s, clinical investigators at Brigham and Women’s Hospital have led the development of a number of drugs for treating rheumatoid arthritis (RA). Thanks to methotrexate and additional progress in the decades since it was approved, the majority of people with RA now experience effective disease management.

“I can confidently say that treatments for RA today are very effective and will continue to improve going forward,” said Elena M. Massarotti, MD, of the Brigham’s Division of Rheumatology, Inflammation and Immunity. “But there are still challenges to overcome.”

One of the biggest of these challenges is that despite effective therapies, 30 percent of patients are unable to achieve complete disease control. This reality drives the continued focus on research into the causes and drivers of RA and the search for additional drugs.

“About one-third of patients with RA go into remission with methotrexate alone,” said Michael E. Weinblatt, MD, co-director of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at the Brigham. “Many more can achieve remission with the addition of other drugs. But we still have about 10 percent of patients with high disease activity, and another 20 percent with disease activity in the moderate range. Their disease has improved, but they’re not where we want them to be.”

Encouraging Signs

Other types of drugs that have greatly improved the treatment of RA by targeting the chronic inflammation that leads to the disease include inhibitors of tumor necrosis factor, inhibitors of IL-6, T cell costimulatory blocking agents, B cell depleting agents and new oral agents that block inflammation.

Controlling RA in a timely fashion is vital because structural damage caused by the inflammation progresses over time. “Fortunately, the need for surgery in people with RA is much less common than it was 15 or 20 years ago,” Dr. Massarotti said. “I’m sending fewer and fewer people for joint replacements. This is because the medical treatments have gotten so much better.”

The Brigham sees about 4,500 people with RA every year. This high volume gives its rheumatologists insights into what works as well as where further research is needed. A patient registry called the Brigham and Women’s Hospital RA Sequential Study (BRASS) also contributes to advances in clinical research for RA.

“We’ve enrolled about 1,500 patients in this registry,” Dr. Weinblatt said. “Some of them have been followed for more than 18 years. It’s greatly increased our understanding of the pathogenesis of the disease and of which factors are active in RA. It also allows us to study the side effects of these drugs.”

The registry serves as a clinical database and a sample repository. According to Dr. Weinblatt, more than 80 papers have come out of the BRASS dataset. In addition, the clinical data and samples are made available to investigators from all over the world who are studying RA.

The Search for Genetic Markers

One important goal of the Brigham’s RA team, along with RA investigators more broadly, is developing biomarkers to predict which people will respond to which therapies. “When a patient walks into the exam room, we have no idea which drug or drugs will be best for them,” Dr. Weinblatt said. “We would like to develop programs that can identify for each individual which treatments will work. This includes the search for genetic markers.”

“The Brigham has a long history of treating people with RA, even before methotrexate,” Dr. Massarotti said, referencing the institution’s status as the country’s first teaching hospital devoted to arthritis and other rheumatic diseases. “And we will continue to lead the way into the future.”

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Genomic Research Connects Juvenile and Adult Forms of Arthritis

Source: Brigham and Women's Hospital - On a Mission
Date: 12/23/2019
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Traditionally, juvenile idiopathic arthritis (JIA) has been considered a distinct condition from the types of arthritis seen in adults. But increasingly, research is showing that juvenile and adult forms of arthritis represent a continuum.

“One of the central themes of my recent work has been pointing out the similarities between juvenile and adult forms of arthritis,” said Peter A. Nigrovic, MD, director of the Center for Adults with Pediatric Rheumatic Illness (CAPRI) at Brigham and Women’s Hospital. “The big picture is that these diseases are much more similar than they are different. I think the differences in nomenclature between the two types have been a hindrance rather than a help in understanding disease biology.”

Studying the Genetics of Arthritis

JIA is a blanket term that covers several different subtypes of arthritis. Like adult forms of the disease, it is characterized by symptoms that include pain and swelling of the joints, stiffness and, in systemic JIA, also rashes and fever. In some cases, it can also affect the eyes or internal organs. A case of arthritis is defined as “juvenile” if it appears before the age of 16. Once it develops, however, JIA can continue into adulthood.

At the Brigham, Dr. Nigrovic cares for adults who have JIA. He also sees children with the disease as an attending physician in the Boston Children’s Hospital rheumatology program. Some of his recent research has looked at the genetics of arthritis.

“One of the strongest pieces of evidence that these diseases are similar has to do in particular with the HLA locus on chromosome 6,” said Dr. Nigrovic, who also directs a lab that uses both human specimens and mouse models to study the basic immune mechanisms of arthritis and other rheumatic diseases. “Proteins encoded at this locus control how peptides are presented to T cells, including autoantigens that can trigger arthritis.”

He noted that the particular HLA genes that carry arthritis risk change with the type of arthritis, but are largely shared between adult-onset and childhood-onset forms of the disease. Risk genes outside of the HLA locus are also shared.

In a paper published in Nature Genetics in July 2018, Dr. Nigrovic and his team used a new technique termed SNP-seq to test thousands of candidate genetic variants linked to JIA risk by genome-wide association studies (GWAS). Through this work, they identified 148 candidate functional single nucleotide polymorphisms (fSNPs) that may modulate the binding of regulatory proteins. For fSNPs near the CD40 and STAT4 genes, they were able to confirm the fSNPs and identify specific transcription factors that likely modulate these genes differentially in individuals who carry protective gene variants compared with those who carry variants associated with enhanced disease risk.

“We believe that this approach will allow us to identify particular pathways that drive disease biology,” he said. “And we expect to find the same sets of pathways in children and adults.” He added that once these pathways are fully characterized, it could eventually enable the development of better targeted treatments for disease subtypes in both children and adults.

Developing a ‘Fingerprint’ Would Be Key

One of Dr. Nigrovic’s long-term goals is to identify drugs that would target pathways engaged by the new protein-DNA interactions identified in his lab. By understanding which variants each individual carries, it may be possible to develop a “fingerprint” that will help determine what treatments will be best for each individual with arthritis, irrespective of age of onset.

“We hope to use GWAS data to identify these common pathogenic pathways,” he said. “We’re not there yet, and we’ll need many patient samples to achieve this goal. But between the large volume of patients that we see—as well as our expertise in other related areas of research at both the Brigham and its related institutions—we are well-positioned to make important contributions in this field.”

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Research Efforts Focus on Underactive Bladder, a Common but Poorly Understood Condition

Source: Brigham and Women's Hospital - On a Mission
Date: 12/06/2019
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Physicians have a good sense of the symptoms and causes of overactive bladder, and clear guidelines exist for diagnosis. Thanks to advertising for pharmaceuticals and other products, even many members of the general public are aware of this condition and know that treatments are available.

Underactive bladder (UAB), on the other hand, is a condition that is poorly understood and not well-studied. Currently, a clear definition of what constitutes UAB is lacking. Even most specialists don’t know how to recognize it. This dearth of information is the motivation behind a collaborative research investigation that has been ongoing for over two years. The effort aims to develop patient-reported outcome measures that can ultimately enable research and treatment for UAB.

“There are urodynamic parameters that we think are characteristic of this condition, but we really don’t know much about it,” said Michael O’Leary, MD, MPH, a senior urologic surgeon at the Brigham’s Division of Urology and one of the study’s principal investigators. “Once you have clear guidelines for what constitutes a particular condition, it makes the job of studying it much easier.”

Establishing Metrics to Characterize UAB

The initial goal of the collaboration is to generate a screening method for UAB based on symptoms and then to validate those questions based on what is already known about the condition. Accordingly, the investigators are aiming to develop a questionnaire for UAB that is similar to those established for conditions like erectile dysfunction and chronic pelvic pain syndrome. The project was begun in response to a request from the National Institute of Diabetes and Digestive and Kidney Diseases, which is funding the research.

“Our job is to better characterize UAB,” Dr. O’Leary said. “So the first thing we need to do is to find out what the patient experience is. Because this condition is symptom-driven, having a way to measure patient-reported outcomes will be valuable.”

Early results have identified a number of indicators that are shared with detrusor underactivity, a potential causal factor for UAB. The study so far has collected data on people aged 40 to 89, with the majority over age 70, and has included both men and women. Dr. O’Leary estimated that up to 20 percent of the elderly population may experience UAB, but noted that the condition is so understudied that its frequency is difficult to determine.

The prominent symptoms identified so far include frequent urination, decreased sensation, incontinence and frequently waking to urinate. The fact that many of these symptoms are similar to other bladder disorders makes diagnosis more challenging, the researchers said.

“The classic teaching is that you would expect underactive bladder to look like retention,” said the Brigham’s Elodi Dielubanza, MD, an associate surgeon and a co-investigator in the study. “In reality, when you encounter patients with UAB, it’s a lot more heterogeneous and nuanced. We currently have no way to understand what the expected patterns might be.

“The difficulty in this work is about trying to recognize something that is so poorly understood. We have to work backwards and start with the patient experience first.”

Identifying the Needs of an Undertreated Condition

This study involves researchers in urology and urogynecology at the Brigham and Massachusetts General Hospital. The New England Research Institute is providing expertise in epidemiology and data collection and management.

“Because this condition is not often diagnosed, currently it tends not to get treated,” Dr. O’Leary said. “Some patients who have a poorly contractile bladder may need to do self-catherization, but there is no standard treatment. The pharmaceutical industry is interested in potential development of new drugs. But before any treatments can be developed, we need to know much more about the underlying causes of this condition, in addition to having a way to measure any benefit that may come from treatments.”

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BabySeq project explores impacts of genetic disease testing in newborns

Source: Cell Press
Date: 01/03/2019
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In the 1960s, doctors began screening newborns for a metabolic condition called phenylketonuria (PKU). Since then, dozens of other diseases have been added to the panel of tests given to newborns, most looking for inherited genetic disorders. (The exact number of tests varies by state.)

In the era of increasingly common genomic sequencing, an effort called the BabySeq Project aims to explore the medical, behavioral, economic, and ethical impacts of adding genetic testing to the roster of newborn screenings. Some of the first findings from the project are being reported January 3 in the American Journal of Human Genetics.

“Traditional newborn screening uses biochemical analysis on a small drop of blood to look for a small number of conditions that can benefit from early intervention,” says senior author Alan Beggs, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital and one of the principal investigators for BabySeq. “In contrast, genomic sequencing has the ability to simultaneously analyze thousands of genes that are known to cause disease.

“But the specificity and sensitivity of genetics tests are uncertain and relatively low, and not all of the diseases that we may find are treatable,” he says. “This leads to a potentially complex package of information about a baby. It’s important to look at how people view this information and what the outcomes of having it are.”

The BabySeq study, led by Beggs and Robert C. Green, of Brigham and Women’s Hospital, together with Amy L. McGuire and collaborators at the Baylor College of Medicine, included sequencing of 159 newborns; 127 were healthy, and 32 were being treated in neonatal intensive care units, although not necessarily for genetic conditions. Parents who consented to have their babies tested filled out questionnaires including questions related to family history.

The investigators report that 15 of the babies (9.4%) carried mutations that revealed a risk of diseases that could arise or be managed in childhood, including cardiomyopathy and hearing loss. The investigators say this number was surprising, because none of these results were anticipated based on the infant’s clinical or family history.

“In this study, we focused on reporting gene variants that had substantive evidence to confer risk for disease” says first author Ozge Ceyhan-Birsoy, a clinical molecular geneticist, now at Memorial Sloan Kettering Cancer Center.

With additional parental consent, 85 babies were also tested for certain conditions that arise later in life but for which at-risk individuals could benefit from early screenings and other interventions. Three of them were found to carry gene variants that put them at a higher-than-average risk of adult-onset cancers. Two had variants in BRCA2, and one tested positive for Lynch syndrome.

“This part of the testing was very different from the component that looked at childhood diseases,” Beggs says. “In this case, it alerted the parents that they should also get tested because they were the ones who had more imminent risk. One of the aspects that’s important to highlight with this kind of research is that genetic testing has implications for the whole family.” This is in contrast to other medical testing, he notes, which only informs you about the health of the person having the test.

The BabySeq project aims to look at issues that arise with this kind of testing. The investigators are not proposing that it become part of standard newborn screening at this time. “There are many considerations with offering these tests to individuals,” says co-author Casie Genetti, a genetic counselor at Boston Children’s Hospital. “We plan to follow these babies, as well as their parents and their doctors, to look at how this information gets used and how it impacts health and well-being long term. It will help us to get a pulse on whether this kind of testing is feasible on a larger scale.”

Another aspect to note is that, unlike other definitive screening tests, genetic results are rarely cut and dried. Genomic sequencing can reveal variants in disease-associated genes that confer higher levels of risk, but in some cases, this might lead only to unnecessary worry, as the absolute risk would still be small. In addition, many gene variants have unknown significance, making predictions of their eventual effects difficult. In the current study, the investigators only reported variants that were pathogenic or likely pathogenic if a child was healthy, but variant classifications may change over time as researchers continue to collect long-term data on people who carry them.

“This is one of the reasons it’s important to continue to follow the participants in this study,” Ceyhan-Birsoy concludes.

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The BabySeq Project is jointly funded by the National Institutes of Health’s Human Genome Research Institute and its National Institute of Child Health and Human Development. This research was supported by the National Institutes of Health.

The American Journal of Human Genetics, Ceyhan-Birsoy et al. “Interpretation of genomic sequencing results in healthy and ill newborns: Results from the BabySeq Project.” https://www.cell.com/ajhg/fulltext/S0002-9297(18)30424-5

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Scientists accidentally engineer mice with unusually short and long tails

Source: Cell Press
Date: 01/17/2019
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Researchers from two groups studying mouse development have accidentally created mice with unusually long and unusually short tails. Their findings, publishing January 17 in the journal Developmental Cell, offer new insight into some of the key aspects controlling the development of tails in mice and have implications for understanding what happens when developmental pathways go awry.

“The same regulatory networks that control mechanisms regulating how a body pattern is formed are often coopted for other developmental processes,” says Moisés Mallo, a researcher at Instituto Gulbenkian de Ciência in Lisbon, Portugal, and senior author of one of the two papers. “Studying these networks can give us relevant information for understanding other developmental, or even pathological, processes.”

Both groups’ findings are related to a gene called Lin28, which was already known to have a role in regulating body size and metabolism, among other functions.

“We were trying to make mouse models of Lin28-driven cancer, but we were surprised to find that these mice had super long tails. They had more vertebrae,” says George Daley (@G_Q_Daley), an investigator and dean at Harvard Medical School and senior author of the other paper. His team was studying the Lin28/let-7 pathway, which regulates developmental timing and has been implicated in several types of cancer.

Mallo, on the other hand, was studying a gene called Gdf11, which was already known to be involved in triggering the development of the tail during embryonic development. In his lab, they found that mice with Gfd11 mutations had tails that were shorter and thicker than those of regular mice. “They also contained a fully grown neural tube inside, as opposed to a normal tail that is essentially made of vertebrae,” Mallo says. “We were able to pinpoint the Lin28 and Hox13 genes as key regulators of tail development downstream from Gdf11.”

Both pathways relate to the development of somites, which give rise to important structures associated with the vertebrate body plan. These blocks of cells eventually differentiate into dermis, skeletal muscle, cartilage, tendons, and vertebrae. As mammals develop, the somites are laid down sequentially along the body axis. Lin28 plays a role in regulating the timing of this repetitive process.

“From my perspective, one of the most important findings of our work is that a group of multipotent cells that build both the somites and the spinal cord are regulated by fundamentally different genetic networks and have different cell competences at two consecutive stages of development,” Mallo says. “This finding goes beyond the trunk to tail transition, possibly acquiring relevance in pathological processes like the initiation of metastasis.”

“There are also important implications in this research for understanding evolution,” says Daisy Robinton, a researcher at Harvard and first author of the study from Daley’s lab. “Anterior-posterior axis elongation is an important feature in bilateral animals, and natural selection has created a variety of tail lengths to suit different evolutionary pressures. Until now, little was known about how length is controlled and how the manipulation of genetics can impact morphogenesis.”

Robinton says the next steps for the Daley lab are to address the question of whether Lin28/let-7 acts similarly in other organ systems, as well as to explore more deeply how this pathway influences cell fate decisions during mammalian development.

For Mallo, future work will focus on uncovering further molecular details of how these players modulate the activity of tail bud progenitors and deepening the understanding of how these molecular interactions are mediated.

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Developmental Cell, Robinton et al: “The Lin28/let-7 pathway regulates the mammalian caudal body axis elongation program.” https://www.cell.com/developmental-cell/fulltext/S1534-5807(18)31084-0 DOI: 10.1016/j.devcel.2018.12.016

Developmental Cell, Aires et al: “Tail bud progenitor activity relies on a network comprising Gdf11, Lin28 and Hox13 genes.” https://www.cell.com/developmental-cell/fulltext/S1534-5807(18)31072-4 DOI: 10.1016/j.devcel.2018.12.004