DMD is caused by a mutation in the dystrophin gene, which produces a large protein essential for stabilizing muscle cell membranes that help protect muscle fibers. Without dystrophin, muscle damage occurs and builds, leading to persistent inflammation and fibrosis (scarring). The condition primarily affects boys—occurring in about 1 in 5,000 live male births—and leads to premature death due to respiratory and cardiac muscle weakness. There is currently no cure. 

The research team focused on monocytes (a type of white blood cell) that travel through the blood stream to infiltrate diseased muscles and become inflammatory macrophages, which promote muscle damage and scarring. They previously discovered that blocking monocyte recruitment from the blood circulation temporarily decreased macrophage accumulation, reduced scarring, and improved muscle function in a disease model of DMD. 

“The benefit is transient,” says Lan Zhou, MD, Neurologist-in-Chief at HSS and senior author of the study. “Inhibiting macrophage infiltration alone is not sufficient for controlling chronic muscle inflammation, which contributes to muscle damage and fibrosis,” 

To uncover additional factors driving macrophage accumulation, the investigators used state-of-the-art technologies, including single-cell RNA sequencing analysis and lineage tracing, to determine the key mechanism that is responsible for fueling chronic inflammation after macrophage infiltration is blocked. 

According to the newly published research, Dr. Zhou and her colleagues discovered that mesenchymal stromal cells (a type of stem cell) in muscle tissue called fibro/adipogenic progenitors (FAPs) produce cytokines or growth factors known as colony-stimulating factor (CSF-1). CSF-1 stimulates resident macrophages in skeletal muscles to proliferate and accumulate, which contributes to chronic inflammation and muscle dystrophy. The findings uncover a new function of FAPs that fuels chronic inflammation and promotes DMD disease progression. 

The researchers concluded that it might be equally important to suppress resident macrophage expansion and activation in addition to inhibiting macrophage infiltration. 

“That means that in order to control chronic muscle inflammation and improve muscle function in patients with DMD, both macrophages and FAPs may need to be targeted,” explains Dr. Zhou. 

As a next step, Dr. Zhou and her team are planning to study the safety and efficacy of a combination therapy using two existing drugs developed for other conditions. One is used to treat chronic inflammation by suppressing macrophage infiltration. The other is a CSF-1 inhibitor used to treat a type of joint tumor that consists of many macrophages due to excessive CSF-1. 

Limited treatment options exist for patients with DMD. Researchers continue to refine gene therapy and cell therapy approaches for DMD, which have so far shown limited success in clinical trials. 

“Experts in the field believe that patients will ultimately require a combination of treatment approaches, not only to correct genetic defects, but also to improve the diseased muscle tissue environment, making the gene and cell therapies more effective,” says Dr. Zhou. “Targeted drugs could be used to treat the inflammatory and fibrotic tissue environment so that healthy genes or cells can be efficiently engrafted, survive, and function.” 

There are currently no objective biomarkers for concussion, an invisible injury and form of mTBI, which often remains difficult to diagnose and treat. Although there are broad consensus guidelines, individual treatment decisions for this heterogeneous injury are largely left to the discretion of the physician. Previous studies have suggested a link between C-reactive protein (CRP), an inflammatory biomarker in the blood, and TBI, but the relationship is still under-explored. Because the underlying pathophysiology remains poorly understood, it remains challenging to create a treatment plan, noted Ayse Erdemir, clinical research coordinator at HSS, and first author of both studies.

“Currently there are no established pharmacological treatments for mTBI,” Erdemir noted. Standard treatment involves physical therapy, guided exercise, and lifestyle modifications, with some options for treating headache, head pressure, and insomnia, common symptoms that can impact recovery. While previous studies of amitriptyline in this population have been inconclusive, the team's research provides new data which may support its use in specific circumstances.

These studies, if further validated, have the potential to influence the treatment of mTBI, she added.

For the first retrospective study of 383 concussion patients, researchers focused on measurements of high sensitivity CRP (hsCRP), an inflammatory biomarker in the blood. Erdemir pointed out, “We found that higher levels of hsCRP were associated with more frequent reporting of symptoms like sadness and trouble falling asleep. Notably, patients with abnormal hsCRP took longer to recover compared to those with normal levels. These patients also tended to be older and have higher BMI.”

Additionally, she said "The findings suggest that hsCRP could potentially be a candidate for inclusion in biomarker panels for acute mTBI assessment, but more research is needed to understand its long-term role in tracking symptom resolution and recovery."

The results also offer a possible new insight into the pathophysiology of the disease, suggesting that, at least in some patients, the concussion may be characterized by low levels of inflammation in the brain that resolves with tailored treatment paradigms.

For the second study, the researchers analyzed data from the same group of patients, focusing on those who were prescribed amitriptyline. They found that patients who had received the drug more often had histories of depression, anxiety, and migraines, and also had more severe concussion symptoms than those who did not receive the medication. Even though their concussions appeared to be more complex and severe, patients in the amitriptyline group recovered at the same rate as more straightforward cases.

“Amitriptyline seems to play a supportive role in helping patients with more frequent and severe baseline symptoms to recover,” said Erdemir. “A tool to treat headache and insomnia in concussion patients doesn’t just improve quality of life throughout recovery; it may also facilitate and potentially expedite recovery. Restoring normal sleep and improving sleep quality is especially important to helping the brain heal from mTBI.”

While researchers believe patients with more severe concussions are more likely to benefit, the drug may still be prescribed in other patients to relieve symptoms.

More research is clearly needed to develop clinical applications. Researchers hope to follow up by analyzing longitudinal trends of hsCRP across recovery, to further support its use as a biomarker. Additional study of amitriptyline should include a randomized, controlled trial comparing the medication to placebo as well as other medications used to treat headache.

References:

High-sensitivity C-Reactive Protein (hsCRP): Retrospective Study of Potential Blood Biomarker of Inflammation in Acute Mild Traumatic Brain Injury (mTBI)

Authors: Guzide Ayse Erdemir, Niluckshi Pitigala, Joseph T. Nguyen, Teena Shetty, MD, MPhil, FAAN (HSS).

Amitriptyline for Acute Mild Traumatic Brain Injury (mTBI)

Authors: Guzide Ayse Erdemir, Niluckshi Pitigala, Joseph T. Nguyen, Teena Shetty, MD, MPhil, FAAN (HSS).

Dr. Memtsoudis succeeds Gregory A. Liguori, MD, who has led the department with distinction for the past 21 years. As Chief Emeritus, Dr. Liguori will focus on his practice at HSS, continue to chair the Credentials Committee and teach as a Professor at Weill Cornell Medicine, and maintain his roles on the Medical Board, Physician Practice Committee, and MIAC.

Dr. Zhou will succeed Interim Chair Matthew E. Fink, MD, who will return full-time to his role as Chairman of the Department of Neurology at Weill Cornell Medicine and Neurologist-in-Chief at NewYork- Presbyterian Hospital/Weill Cornell Medical Center.  Dr. Fink accepted HSS’ request to serve as interim leader following the retirement of Dale J. Lange, MD, who led the department for 13 years.  Dr. Zhou will lead the continued advancement of HSS’ Neurology Department in collaboration with Weill Cornell Medicine Neurology.

"Drs. Fink and Ligouri have provided instrumental support for their clinical colleagues exemplifying excellence in medicine—HSS is grateful for their leadership," said Bryan T. Kelly, MD, MBA, President and CEO, HSS. "We are thrilled to have the expertise and stewardship of Dr. Zhou and Dr. Memtsoudis in advancing translational and clinical research programs that will serve the needs of all of our patient populations. Their collaborative approaches to musculoskeletal health will strengthen our multidisciplinary services and further improve patient care and recovery."

"HSS is recognized as a leader in musculoskeletal health because of the unparalleled number of talented and accomplished experts who call it home," said Douglas Padgett, MD, Surgeon-in-Chief and Medical Director at HSS. "The appointments of Dr. Memtsoudis and Dr. Zhou embody our tradition of strong leaders committed to addressing pain and movement challenges, continuing the advancement of our rich clinical pipeline toward improved health and wellness for everyone."

Stavros Memtsoudis, MD, PhD, MBA

Dr. Memtsoudis is board-certified in anesthesiology and critical care medicine. He earned his medical degree and PhD from Georg-August-University Medical School, in Goettingen, Germany, in 1999, and his MBA from the University of Massachusetts in 2018. Dr. Memtsoudis joined HSS after completing subspecialty training in critical care medicine, cardiac care, and thoracic anesthesiology. He is widely recognized for his clinical expertise in the perioperative care of orthopedic patients with advanced cardiovascular and pulmonary disease as well as his prolific research into perioperative care. During the height of COVID-19, elective surgeries, such as hip and knee replacements, were canceled to accommodate patients requiring hospital admission. Dr. Memtsoudis was instrumental in leading musculoskeletal medical teams at HSS in managing critical care patients.   

As a senior scientist, Dr. Memtsoudis directs research initiatives on cardiopulmonary physiology and population-based outcomes research. His findings have been published in more than 380 peer-reviewed articles. Due to his prominence in the field of perioperative research, Dr. Memtsoudis has won several prestigious research awards, frequently lectures on the topic, and serves on anesthesia and pain medicine boards nationally and internationally. 

"Excellence and continuity of patient care are our highest priorities at HSS," said Dr. Memtsoudis. "I have the pleasure of being a member of an incredible team of experts, and I'm equally passionate about working alongside internationally prominent clinician-

scientists who prioritize delivering the highest-quality care to all our patients."

Dr. Memtsoudis's new role is effective immediately.

Lan Zhou, MD, PhD

Dr. Zhou is a nationally renowned neuromuscular specialist with a long history of clinical and academic accomplishments. She earned her medical degree from Shanghai Medical University School of Medicine in China (now Fudan University Medical Center) in 1989 before completing her PhD in developmental biology at the University of Cincinnati College of Medicine in 1995. Previously, Dr. Zhou served as a staff neurologist at Cleveland Clinic, an associate professor of neurology, neurosurgery, and pathology at Icahn School of Medicine at Mount Sinai, and a professor of neurology and neurotherapeutics and pathology at the University of Texas Southwestern Medical Center. She comes to HSS from Boston University School of Medicine, where she has served as a professor of neurology and pathology and Vice Chair for Research in the Department of Neurology. 

Dr. Zhou cares for patients with neuromuscular diseases and regularly performs and interprets nerve, muscle, and skin biopsies as part of her practice. She has special interests in small-fiber neuropathy, inflammatory myopathy, myasthenia gravis, and neuromuscular pathology. Additionally, she is recognized as an outstanding educator and muscle research scientist. She runs a National Institutes of Health–funded research program to study muscle inflammation, fibrosis, and regeneration associated with skeletal muscle injury and repair. In her new role at HSS, she will establish a clinical diagnostic neuromuscular pathology laboratory.

"I'm honored to take on this new role, building upon and developing new programs that will continue to serve the diverse patient communities at HSS," said Dr. Zhou. "My passion is to make a meaningful impact in the lives of patients and families living with neuromuscular diseases and to work with musculoskeletal teams to develop effective treatments to help them live better."

Dr. Zhou's new role is effective March 1, 2024. 

HSS Midtown’s medical services include diagnosis of musculoskeletal issues, physical therapy, digital X-ray and non-surgical care, as well as convenient access to care coordination and evaluations, follow-up and post-surgical care for patients undergoing surgical procedures at other HSS locations. “HSS Midtown is designed to overcome many of the reasons why too many people are enduring unnecessary pain and impairment,” said HSS Physiatrist-in-Chief Joel M. Press, MD. “An integrated team of non-surgical and surgical specialists, in a gorgeous new midtown location where you can book directly, open also evenings and on Saturdays.”

“HSS has been part of the fabric of midtown Manhattan for more than 100 years, since long before the capabilities of this new location were imaginable,” said Louis A. Shapiro, President and CEO of HSS. “With our 18th location, plus virtual care, HSS quality is now within a few clicks or a few miles of most people who live or work in New York, New Jersey, Connecticut or Florida.”

An entire floor of HSS Midtown is dedicated to Rehabilitation and Performance services, including hand therapy, occupational therapy and performance training. State-of-the-art technologies include the only FDA-certified markerless motion capture system, which aids in analyzing the quality of a person’s movement and guiding injury prevention. Other integrative medicine services, including acupuncture, massage therapy and Pilates, will be offered by trained HSS experts to complement and optimize patients’ overall health.

“The breadth of services offered at HSS Midtown means our patients will be able to meet multiple needs in one location,” said Dr. Press. “Our goal is to provide comprehensive care for all patients’ musculoskeletal needs.”

Saturday and evening hours are available at HSS Midtown. To schedule an in-person or virtual visit, call 646.618.7777 or visit HSS.edu/Midtown.

Correspondent Scott Pelley interviews multiple sources who have been suffering from symptoms including Mark Lenzi, a State Department security officer, who worked in China.

Teena Shetty, MD, neurologist at HSS, recalls that while Lenzi did not have any history of trauma, he reported a number of neurologic symptoms characteristic of mild traumatic brain injury.

"The presumption is that something happened which caused a functional brain injury of widespread brain networks because he has symptoms to reflect a multitude of brain networks," explains Dr. Shetty.

Watch the full segment at CBSNews.com. This also aired on March 17, 2019.
 

"The biggest part of all of this is education and the fact that the athletes are more aware of the symptoms and what to expect," Erin E. Manning, MD, neurologist at HSS, explains. "I think a lot of this depends on their reporting of the symptoms. If you can't get the athletes to buy into all of it, then all of the awareness you can have is not going to be helpful."

She notes that more tests are needed to diagnose concussions.

"That's the most important thing, if there is some objective test that can be developed that can diagnose via blood test or a certain kind of brain imaging," Dr. Manning says. "That would be very helpful and probably one of the more valuable things that can be done at this point, other than prevention."

Read the full article at UPI.com.

Erin E. Manning, MD, neurologist at HSS, explains that there is still much about CTE that researchers do not fully understand.

"We don't know why people get CTE. I think the most that it's been looked at is in football players, but all we know is what the brain looks like after they die. We don't know what happens during people's lives. We also don't know how the findings correlate with people's symptoms," says Dr. Manning.

She states that there is a lot of research that needs to be done as there is no established link between football and CTE, nor concussions and CTE.

"The [existing] studies have been mostly observational. In science, we consider the gold standard to be randomized controlled studies," said Dr. Manning, who points out that this topic does not lend itself to that type of study.

Read the full article at DailyMail.co.uk.

He reports that Hunt is the modern-day major league leader in getting hit by a pitch with a total of 243 over his 12 season career.

"If we're looking specifically at head injuries in athletes, the data is showing that, per year [of playing], there's a 20 to 30 percent increased risk overall [of getting Parkinson's]," said Alexander Shtilbans MD, PhD, MS, neurologist at HSS.

Dr. Shtilbans explains that the disease progresses to the point where people cannot walk and also impacts their memory and speech.

Read the full article at NYPost.com. This also appeared in the November 16, 2018 print edition.

Dr. Manning, who did not treat Gronkowski, said it is likely he can recover in time for the Super Bowl, which is two weeks away.

"The minimum [recovery time] is five days," Dr. Manning noted. However, she explained that most people need seven days or more.

"The next few days will tell. If you see him at practice in a few days, and running, that's a good sign."

Read the full article at providencejournal.com. This article also appeared in the January 23, 2018 print issue.

Additional Coverage:

• The Union Leader: Doctors bet Gronkowski will be ready. This appeared in the January 24, 2018 print issue.