Study Identifies New Targets for Huntington’s Disease Research

Ghazaleh Sadri-Vakili, PhD, is the director of the NeuroEpigenetics Laboratory at Massachusetts General Hospital’s Institute for Neurodegenerative Diseases (MIND).  Her work investigating the genetics of Huntington’s disease was recently featured in an article on the Mass General Giving website.

Here are five things to know:

  1. Huntington’s disease (HD) is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. Symptoms typically start occurring between the ages of 30 and 50. The disease is highly heritable—each child of a parent with HD has a 50% chance of inheriting the faulty gene.
  2. According to the Huntington’s Disease Society of America (HDSA), symptoms of HD typically begin with a loss of coordination and cognitive skills. These declines get more pronounced as the disease progresses. In late stages, HD patients lose the ability to walk and speak, and choking becomes a major concern. Death is typically due to complications from the disease and not the disease itself.
  3. Researchers at Massachusetts General Hospital have been at the forefront of research into the genetic underpinnings of Huntington’s disease for the past two decades. In 1983, a team led by James Gusella, PhD, identified the section on chromosome 4 where the HD gene was located. In 1993, a multi-institutional research group that included Marcy E. MacDonald, PhD, and Dr. Gusella identified the gene itself.
  4. Recently, a research team led by Ghazaleh Sadri-Vakili, PhD, has been studying how gene expression differs in patients with HD. Her team has identified two ways in which a genetic pathway known as the Hippo pathway malfunctions in HD. These malfunctions cause HD patients to produce too much of an enzyme called MST, and not enough of a protein called YAP.
  5. If researchers are able to identify drugs that correct this imbalance, they may be able to develop treatments that slow or halt the progression of the disease.

Wireless Sleep Monitoring System Could Make Sleep Studies Much Easier

If you find yourself tossing and turning all night, or hitting snooze a few too many times each morning, you’re not alone. More than 50 million Americans suffer from sleep disorders, and these sleep issues can get worse in individuals with Parkinson’s and Alzheimer’s disease.

Researchers from MIT and Mass General recently unveiled a wireless, portable system for monitoring individuals during sleep that could provide new insights into sleep disorders and reduce the need for time and cost-intensive overnight sleep studies in a clinical sleep lab.

Here are five things to know:

  1. Sleep disorders are typically diagnosed by bringing a patient into an overnight sleep lab, hooking them up to electrodes, and monitoring their brain activity while they sleep. While this process is effective, it is also limiting. Individuals with sleep disorders may have even more difficulty sleeping when they are hooked up to wires and in the artificial setting of a sleep lab.
  2. To make it easier to diagnose and study sleep problems at home, researchers at MIT and Mass General have created a new system for measuring sleep that is wireless, portable and powered by artificial intelligence.
  3. The system consists of a laptop-sized device that emits low frequency radio waves while an individual is sleeping. The device then measures changes in those waves that are caused by shifts in movement and breathing patterns in sleeping individuals. The device then uses an advanced algorithm—powered by artificial intelligence—to translate these changes into the different stages of sleep, including light, deep and rapid eye movement (REM).
  4. In a test of 25 healthy volunteers, the new system proved to be 80 percent accurate in identifying sleep stages, which is comparable to the accuracy of a sleep specialist reading EEG measurements, according to the research team
  5. The team is now planning to use their system to investigate how Parkinson’s disease affects sleep. Future research projects could look into common sleep disorders such as insomnia and sleep apnea, investigating how sleep is affected by Alzheimer’s disease, and detecting epileptic seizures that occur during sleep.

Researchers involved in this work are Dina Katabi, the Andrew and Erna Viterbi Professor of Electrical Engineering and Computer Science at MIT, Matt Bianchi, chief of the Division of Sleep Medicine at Mass General, and Tommi Jaakkola, the Thomas Siebel Professor of Electrical Engineering and Computer Science at MIT. Mingmin Zhao, an MIT graduate student, is the paper’s first author, and Shichao Yue, another MIT graduate student, is also a co-author.


New AI algorithm monitors sleep with radio waves (MIT News)

Image credit: Christine Daniloff/MIT

Sniffing Out the Root Cause of Malnutrition in Patients with Kidney Disease

Nigwekar quoto (1).png

Have you noticed that your sense of taste can get thrown off when you’re sick with a stuffy nose? That’s because the majority of a food’s flavor comes from our ability to smell it.

Could a similar connection between smell and taste explain why kidney disease patients often lose their interest in food, reporting that it has little flavor or an unpleasant taste? In a recent study published in the Journal of the American Society of Nephrology, Massachusetts General Hospital researchers share new findings about the link between loss of appetite and loss of smell in these patients.

Here are five things to know:

  1. More than 25 million adults in the U.S. have chronic kidney disease, with more than half a million requiring dialysis. While kidney disease is challenging enough on its own, many patients also suffer from malnutrition at the same time. “Poor dietary intake leading to malnutrition is common in these patients, but there currently are no effective treatments addressing these complications,” says first author Sagar Nigwekar, MD, of the Mass General Division of Nephrology. Despite the known connection between sense of smell and taste, little research has been done to investigate the impact of loss of smell on nutrition in patients with kidney disease.
  1. To better understand this potential association, Nigwekar, senior author Teodor Păunescu, PhD, also of Mass General Nephrology, and their team enrolled 160 participants with either end-stage kidney disease on dialysis, chronic kidney disease not yet at the end stage, or healthy control subjects with neither condition. Participants were tested on their ability to identify specific odors as well as the threshold at which they could detect a smell.
  1. The study found that those with end-stage kidney disease had greater abnormalities in their sense of smell. Specifically:
  • Based on the odor identification tests, almost 70 percent of those with chronic kidney disease and about 90 percent of those with end-stage disease had a significant reduction in their sense of smell.
  • In the test determining odor detection thresholds, participants with end-stage kidney disease required a four times greater concentration of an aroma in order to detect it than those with chronic disease or control participants.
  • In all three groups, participants’ nutritional status – determined by a standard assessment of food intake and weight changes, among other factors –correlated with their ability to smell. Those with a better sense of smell had a better nutritional status.
  • Interestingly, across all three groups, participants’ ratings of their own sense of smell was about the same despite what the laboratory tests showed. Self-assessment scores averaged 80 percent on a scale of 0 to 100, suggesting that most patients were not aware of having problems with their sense of smell.
  1. In the hopes of identifying a potential treatment to improve sense of smell, the team also conducted a small pilot study testing daily intranasal doses of theophylline – a drug approved to treat asthma and emphysema and previously reported to reduce similar sense of smell issues in patients without kidney disease. They found this treatment strategy increased the ability to smell odors in five of the seven participants with dialysis-dependent, end-stage kidney disease.
  1. The team now plans to conduct larger studies to determine the sequence of events between changes in sense of smell, changes in food consumption, and the eventual onset of malnutrition in patients with end-stage kidney disease. They are also excited about further exploring the potential of using drugs such as theophylline to treat kidney disease patients and prevent malnutrition.

Read more in this Mass General press release

Could a Technique Echoing an Ancient Greek Military Strategy Point the Way to More Effective Cancer Treatments?

Trojan horse

According to Greek legend, the Trojan horse was a wooden structure built by Greek soldiers and presented to the Trojans as a gift after a long and fruitless siege of the city during the Trojan War. When the Trojans brought the gift horse within their city walls, the Greek soldiers who were hidden inside crept out under the cover of night and launched a deadly surprise attack. Historians continue to debate how much of the tale is based in fact and how much in myth.

At Massachusetts General Hospital, a real-life Trojan horse scenario that takes place on the nanoscale level could provide a way to sneak cancer drugs into fortified tumor cells so the drugs can attack from within.

Here are five things to know about a new study from the Mass General Center for Systems Biology:

    1. 1. Think of nanoparticles as the Trojan horses of cancer therapy. These tiny molecules (typically between 20 and 100 nanometers in size) are increasingly being used to transport drugs to a specific target in the body. The ability that researchers have to easily change the size and surface characteristics of the nanoparticles and control the time and location of the drug’s release makes them ideal for drug delivery systems.
    1. 2. Nanoparticles are small enough to carry the drugs (the Greek soldiers) through the body and can protect the encapsulated drug from toxic substances in the bloodstream that are used in infusion chemotherapy. However, in clinical practice, getting these nanoencapsulated drugs into patients’ tumors has been challenging—tumor blood vessels are difficult to break through, which limits the passage of any drugs from the bloodstream into tumor cells. Although it’s usually beneficial for blood vessels to maintain barrier function, their tough exteriors are a disadvantage in cancer therapies.
    1. 3. A 2015 study by Miles Miller, PhD, of the Center for Systems Biology, and his colleagues showed that tumor-associated macrophages — immune cells found around tumors that are in charge of engulfing pathogens, foreign materials and dead cells — can improve delivery of nanoparticle-based therapies to tumor cells. They also found that radiation therapy made it easier for substances to pass through tumor blood vessels. But exactly how these effects are produced and how they could be combined to enhance nanomedicine delivery was not known. Answering those questions was the goal of the current study.
    1. 4. Miller and his team found that macrophages can be prompted to act like Trojans, helping to bring the drugs inside the tumor, if the tumors are treated with radiation prior to administering the drugs. In the same way that a siege weakens the resistance of a city, the radiation weakens the blood vessels within the tumor. It also increases the number of macrophages attracted to tumor blood vessels which, in turn, pick up the drug-laden nanoparticles and bring them into the tumor. The sudden influx of macrophages into the weakened walls of the blood vessels causes many of the vessels to burst, thus flooding the tumor cells with the drug-laden nanoparticles and improving drug delivery by 600 percent.
    1. 5. “Finding that this combination of radiation and nanomedicine leads to synergistic tumor eradication in the laboratory provides motivation for clinical trials that combine tumor rewiring using radiation therapy with nanomedicine,” says Miller, who was lead author of the study. “Most of the treatments and nanomedicines employed in this study are FDA approved for cancer treatment, so this combination treatment strategy could be tested in clinical trials relatively quickly.”


    Radiation & Macrophages

  1. Ralph Weissleder, MD, PhD, Director of the MGH Center for Systems Biology is senior author of the Science Translational Medicine paper.

More Than Meets the Eye: Researchers Find Eye Contact Causes Stress and Overactivation in the Brains of Autistic Individuals

They say that eyes are the windows to the soul, but for individuals with autism, a lack of eye contact can reveal much more. A team of investigators based at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital has shed light on why those with autism often avoid looking others in the eyes.

Here are five things to know about the study published in Nature Scientific Reports this month:

  1. Individuals with autism often find it difficult to look others in the eyes. Many say that maintaining eye contact is uncomfortable or stressful for them – some will even say that “it burns” – which suggests the root of this discomfort is neurological.
  2. Previous work by Nouchine Hadjikhani, MD, PhD, Director of Neurolimbic Research in the Martinos Center and corresponding author of the new study, demonstrated that the subcortical system, the part of the brain activated by eye contact and responsible for processing emotions and facial recognition, was oversensitive to direct gaze and emotional expression in autistic individuals.
  3. In her most recent study, Hadjikhani presented images of faces conveying different emotions to study subjects with and without autism and measured their brain activity via functional magnetic resonance imaging (fMRI). When both groups were able to gaze at the images freely, there was no difference in subcortical activation.
  4. When the test was changed to narrow the focus to the eyes, Hadjikhani observed overactivation of the subcortical system in participants with autism. Images of fearful faces prompted the most significant response, but happy, angry and neutral faces had an effect as well. Their results support the idea that there is an imbalance between the brain’s “excitatory” network, which reacts to stimulation, and inhibitory network, which calms it down.
  5. The findings suggest that behavioral therapies that try to force individuals with autism to make eye contact could be counterproductive. A better approach may be to slowly introduce these individuals to eye contact so they can learn strategies for managing the accompanying sensations.


Autism and eye contact

Children’s Sleep Habits Could Improve Their Ability to Focus, Make Friends and Solve Problems Later on in Childhood: Five Things to Know

A recent study by the MassGeneral Hospital for Children found that children ages 3 to 7 who don’t get enough sleep are more likely to have problems with attention, emotional control and relationship building later on in childhood. Here are five things to know about the study…

Young boy sleeping on bed with teddy bear

  1. The recommended amount of sleep for children is 11 hours or more at ages 3 to 4 year; and 10 hours or more at ages 5 to 7 years.
  2. A recent study from MassGeneral Hospital for Children reports that children ages 3 to 7 who don’t get enough sleep are more likely to have problems with attention, emotional control and peer relationships in mid-childhood (ages 7-10). The study found significant differences in the surveys responses of parents and teachers depending on how much sleep the 7-year-old children regularly received at younger ages.
  3. Analyzed data came from Project Viva, a long-term study that looks at the health impacts of several factors during pregnancy and after birth.  Information was gathered from mothers via interviews and questionnaires conducted at varying time points between when children were ages 6 months and 7 years old. Mothers and teachers were also sent surveys evaluating factors such as emotional symptoms and problems with conduct or peer relationships, when children were around 7.
  4. Among the 1,046 children enrolled in the study, those living in homes with lower household incomes and whose mothers had lower education levels were more likely to sleep less than nine hours at ages 5 to 7. Other factors associated with insufficient sleep include more television viewing and a higher body mass index. Sleep deficiencies also tend to be more prevalent in African American children. Sleep levels during infancy often predict levels at later ages, supporting the importance of promoting a good quantity and quality of sleep from the youngest ages.
  5. “Our previous studies have examined the role of insufficient sleep on chronic health problems – including obesity– in both mothers and children,” explains Elsie Taveras, MD, MPH, chief of General Pediatrics at MassGeneral Hospital for Children, who led the study.  “The results of this new study indicate that one way in which poor sleep may lead to these chronic disease outcomes is by its effects on inhibition, impulsivity and other behaviors that may lead to excess consumption of high-calorie foods. It will be important to study the longer-term effects of poor sleep on health and development as children enter adolescence.”

You can read more about this study here. And in honor of #WorldSleepDay today, check out this great article from the American Academy of Sleep Medicine that offers tips on helping your child get a better night’s rest.

Five Things to Know: The Effects of Acupuncture on Carpal Tunnel Syndrome

Person holding wrist in pain

In a new study reported in the journal Brain, investigators at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital shed new light on how acupuncture provides measureable improvements for chronic pain patients. Here are five things to know:

  1. Acupuncture is a therapy that originated in China several thousand years ago that involves sticking tiny needles into the body in an effort to produce a variety of beneficial health effects, primarily pain relief. Studies exploring acupuncture’s effect on chronic pain disorders have shown that it may be marginally better than a placebo in reducing patient-reported pain, but researchers still want to know exactly how does acupuncture work? And is it any better at improving measurable objective outcomes for chronic pain?
  2. To get to the root of these questions, investigators at Mass General looked at the connection between acupuncture and carpal tunnel syndrome (CTS), a nerve pain disorder. Why CTS? It’s one of the few chronic pain disorders associated with objective measurable changes in the body. Because CTS is a result of compression of the median nerve in the arm, impulses between the wrist and the forearm, such as motor function and sensation, are slowed down. Additionally, studies have shown that the brain – particularly the part that receives touch-related signals – is remapped in CTS. Specifically, brain cells that usually respond to touch signals from individual fingers start to respond to signals from multiple fingers.
  3. The study split 80 participants with CTS into three groups that received one of three treatments: electro-acupuncture at the affected hand, electro-acupuncture at the ankle opposite the affected hand, or sham electro-acupuncture with placebo needles near the affected hand. Results were measured before and after eight weeks of therapy sessions (16 sessions in total) using a questionnaire and MRI scans.
  4. Researchers found that participants in all three groups reported improvements in the pain and numbness they were feeling after the treatments. However, there were notable differences in physiologic measures. Participants who received real acupuncture either at the affected hand or at the ankle saw improved nerve impulses in the wrist. Additionally, only those that received real acupuncture at the affected hand experienced brain remapping that was also linked to long-term improvement in CTS symptoms. No physiologic improvements resulted from sham acupuncture.
  5. Researchers plan to follow up this study with further research linking objective/physiological and subjective/psychological outcomes for acupuncture-produced pain relief. Better understanding of how acupuncture works to relieve pain – and the ability to point to objective scientific measures demonstrating its effectiveness – could help to improve non-pharmacological care options for chronic pain patients.

Vitaly Napadow, PhD, director of the Center for Integrative Pain Neuroimaging at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital is senior author of this study. Read more here.

Five Things To Know: New Therapy for Dangerous Swelling Disorder

Monoclonal y-shaped antibodies

Researchers from the Massachusetts General Hospital Division of Rheumatology, Allergy and Immunology recently came out with a study published in New England Journal of Medicine. Here are five things to know:

  1. Hereditary angioedema (HAE) is a rare but serious condition passed down through families. HAE affects the blood vessels and is caused by a low level or improper function of a protein called the C1 inhibitor.
  2. HAE causes rapid swelling, particularly in tissues in the face, hands, gastrointestinal tract and airway. The uncontrolled swelling not only restricts movement, sometimes for several days, but also can be life-threatening when the airway is involved. While it’s important to treat the swelling during an HAE attack, preventing attacks would be beneficial for many patients. However, current FDA-approved preventive treatments have limitations.
  3. HAE patients participating in this clinical trial (37 total) received either two shots of an antibody called lanadelumab 14 days apart, or a placebo. The strength of the shot varied from 30 to 400 mg and results were analyzed for the 8-50 days following treatment.
  4. Researchers found that from day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer HAE attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group. Reports of pain at the injection site and headache were similar across all groups, and no serious side effects were reported, supporting the safety of the treatment.
  5. “If this kind of efficacy is seen in the larger phase 3 trial, which is now underway here at Mass General and many other sites, this could significantly improve the quality of life for patients with HAE,” says Aleena Banerji, MD, corresponding and a lead author of the NEJM. 

Learn more about this study here.

Five Things to Know: The Blood-Brain Barrier, Intestinal Permeability and Autism

In this new series, we’ll provide you with five things you need to know about breaking research at Massachusetts General Hospital.

Researchers from the Center for Celiac Research and Treatment at Massachusetts General Hospital and the Mucosal Immunology and Biology Research Center at MassGeneral Hospital for Children (MGHfC) recently came out with a study published in Molecular Autism. Here are five things to know:

  1. Autism spectrum disorder (ASD) is the fastest-growing developmental disability in the U.S., with 1 in every 68 children born in this country diagnosed with ASD. Parents and researchers alike are looking for both the causes and treatment options for this complex condition.
  2. The blood-brain barrier prevents materials in the blood from entering the brain, and intestinal epithelial tissue (the intestine’s lining) creates a boundary between the intestine and its external environment. When either of these two barriers isn’t functioning properly, it can lead to inflammation in the body.
  3. Researchers from the Center for Celiac Research and Treatment at Mass General and the Mucosal Immunology and Biology Research Center at MGHfC looked at how the blood-brain barrier and increased intestinal permeability, otherwise known as a ‘leaky gut’, might affect the development of ASD. The study involved analyzing postmortem brain tissues from 33 individuals (8 with ASD, 10 with schizophrenia and 15 healthy controls) and intestinal tissues from 21 individuals (12 with ASD and 9 without such disorders).
  4. The results showed alterations in both blood-brain barrier and intestinal permeability in individuals with ASD. This is the first time anyone has shown that an altered blood-brain barrier and impaired intestinal barrier might both play a role in inflammation of the nervous tissue in people with ASD.
  5. What’s next? Researchers plan to look at how microbiota, the collection of microorganisms in the gut, are linked with leaky gut and behavior. Researchers already know that kids with ASD have an altered composition of gut microbial communities. If they can figure out what is required or missing, then they can come up with a treatment that might be able to improve some of the behavioral issues and/or the gastrointestinal symptoms.

Learn more about this study here.