A new way of thinking about tau kinetics, an essential component of Alzheimer’s disease

Source: Cell Press
Date: 03/21/2018
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Alzheimer’s disease is most often characterized by two different pathologies in the brain: plaque deposits of a protein called beta-amyloid and tangles of another protein called tau. A paper appearing March 21 in the journal Neuron brings new insights into how tau proteins are processed in the human central nervous system. Researchers found that tau production and secretion from nerve cells appears to be an active process in the natural course of Alzheimer’s disease. This may explain why experimental treatments targeting tau have had disappointing results, as the current focus of these drugs assumes that the protein is primarily released from dying nerve cells.

“This study changes our way of thinking about tau in the context of neurodegenerative diseases,” says senior author, Randall Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis. “Contrary to the idea that tau is a product released by dying neurons, we have shown that the release of tau is an active and controlled activity that appears to be an important part of the disease process.”

In the study, the investigators used mass spectrometry and a method called stable isotope labeling kinetics to study tau in the cerebrospinal fluid (CSF) of people who were known to have Alzheimer’s and healthy controls. This enabled them to measure the tau turnover rate and its half-life in the human nervous system as well as to analyze the different forms of the protein. Their findings revealed that certain forms of tau have faster turnover rates than others, suggesting that they may have unique biological activities. In addition, they found that production rate of tau was higher in people with Alzheimer’s, suggesting a biological link between the presence of amyloid plaques and tau kinetics.

“We’ve known for a long time that CSF tau is increased in Alzheimer’s disease, but until this study, we didn’t know if tau production was increased or if clearance was decreased,” says Chihiro Sato, a member of the Bateman lab and one of the paper’s co-first authors. “Our results showing that tau production is increased suggest that we might want to target tau production therapeutically.”

The researchers also looked at tau production in human neurons made from induced pluripotent stem cells (iPSCs). “The research with the iPSCs was really valuable, because we were able to ask questions about human neurons that we wouldn’t be able to ask in living subjects,” says Celeste Karch, an Assistant Professor of Psychiatry at Washington University School of Medicine and one of the study’s co- authors. “We found that inside neurons some forms of tau are turned over more quickly than others. Interestingly, the forms of tau that are turned over more quickly are also those that are prone to misfold and aggregate in the context of Alzheimer’s disease and other tauopathies.”

“Using mass spectrometry, we found that tau is truncated in CSF in healthy people and Alzheimer’s patients,” says Nicolas Barthélemy, a member of the Bateman lab and the other co-first author. “Truncated tau is released differently from full-length tau, supporting our hypothesis that tau is actively processed under physiological and pathological conditions.”

The investigators say the knowledge gained from this study not only helps to understand more about Alzheimer’s disease, but other diseases characterized by the aggregation of tau as well. “We expect these findings will help us to distinguish between Alzheimer’s and other types of tauopathies in future,” Bateman says. The investigators plan to expand their research to patients with some of these other diseases, including progressive supranuclear palsy and corticobasal degeneration, to determine whether there are different forms of tau in the cerebrospinal fluid and different kinetics underlying the changes that are observed.

“It’s hard to do clinical research on tauopathies right now, because we don’t have good tests for diagnosing these other diseases, such as frontotemporal dementia,” Bateman adds. “Having an accurate diagnosis helps not only in the clinic but also in clinical trials, to ensure that we’ve included the right patients in our studies.”

High-resolution brain imaging provides clues about memory loss in older adults

Source: Cell Press
Date: 03/07/2018
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As we get older, it’s not uncommon to experience “senior moments,” in which we forget where we parked our car or call our children by the wrong names. But currently there are no good ways to determine which memory lapses are normal parts of aging and which may signal the early stages of a severe disorder like Alzheimer’s disease. In a study appearing March 7 in the journal Neuron, researchers report that data from high-resolution functional brain imaging can be used to show some of the underlying causes for differences in memory proficiency between older and younger adults.

“At the fundamental level, we still understand very little about how aging affects the neural systems that give rise to memory,” says Zachariah Reagh, the study’s first author, who is now a postdoctoral fellow at the University of California, Davis.

The paper reports data from 20 young adults (ages 18 to 31) and 20 cognitively healthy older adults (ages 64 to 89). The participants were asked to perform two kinds of tasks in an fMRI scanner, an object memory task and a location memory task. Because fMRI looks at the dynamics of blood flow in the brain, it enables investigators to determine which parts of their brains the subjects are using in each task.

In the object task, participants learned pictures of everyday objects and were then asked to distinguish them from new pictures. “Some of the pictures were identical to ones they’ve seen before, some were brand new, and others were similar to what they’ve seen before–we may change the color or the size,” says Michael Yassa (@mike_yassa), Director of the Center for the Neurobiology of Learning and Memory at the University of California, Irvine, and the study’s senior author. “We call these tricky items the ‘lures.’ And we found that older adults struggle with these lures. They are much more likely than younger adults to think they’ve seen those lures before.”

The second task was very similar but required subjects to determine during test whether objects changed their location. For this type of memory task, older adults fared quite a bit better. “This suggests that not all memory changes equally with aging,” says Reagh. “Object memory is far more vulnerable than spatial memory, at least in the early stages.” Other studies have shown that problems with spatial memory and navigation do manifest as individuals go down the path to Alzheimer’s disease.

Importantly, by scanning the subjects’ brains while they underwent these tests, the researchers were able to establish a mechanism within the brain for that deficit in object memory.

They found that it was linked to a loss of signaling in the part of the brain called the anterolateral entorhinal cortex. This area was already known to mediate the communication between the hippocampus, where information is first encoded, and the rest of the neocortex, which plays a role in long-term storage. It is also an area that is known to be severely affected in people with Alzheimer’s disease.

“The loss of fMRI signal means there is less blood flow to the region, but we believe the underlying basis for this loss has to do with the fact that the structural integrity of that region of the brain is changing,” Yassa explains. “One of the things we know about Alzheimer’s disease is that this region of the brain is one of the very first to exhibit a key hallmark of the disease, deposition of neurofibrillary tangles.”

In contrast, the researchers did not find age-related differences in another area of the brain connected to memory, the posteromedial entorhinal cortex. They demonstrated that this region plays a role in spatial memory, which was also not significantly impaired in the older subjects. “These findings suggest that the brain aging process is selective,” Yassa adds. “Our findings are not a reflection of general brain aging, but rather specific neural changes that are linked to specific problems in object but not spatial memory.”

To determine whether this type of fMRI scan could eventually be used as a tool for early diagnosis, the researchers plan to expand their work to a sample of 150 older adults who will be followed over time. They will also be conducting PET scans to look for amyloid and tau pathology in their brains as they age.

“We hope this comprehensive imaging and cognitive testing will enable us to figure out whether the deficits we saw in the current study are indicative of what is later to come in some of these individuals,” Yassa says.

“Our results, as well as similar results from other labs, point to a need for carefully designed tasks and paradigms that can reveal different functions in key areas of the brain and different vulnerabilities to the aging process,” Reagh concludes.

The Last Frontier in Cancer Care: Treating Disease When It Spreads to the Brain

Source: Memorial Sloan Kettering - On Cancer
Date: 02/16/2018
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Metastatic brain cancer gets far less attention in the media than primary brain tumors, despite being at least ten times more common. Metastatic brain cancer occurs when tumors spread from other parts of the body to the brain. It was once considered an end stage of the disease. Doctors’ main focus was making patients comfortable. But increasingly, metastatic brain cancer is being treated aggressively, with the goal of eliminating it. Memorial Sloan Kettering doctors and scientists are leading the charge to find new and innovative ways to treat this type of brain cancer.

“There used to be this feeling of therapeutic nihilism about metastatic brain cancer. Once cancer spread there, everyone assumed not much could be done,” says Adrienne Boire, a neuro-oncologist who also leads a lab in MSK’s Human Oncology and Pathogenesis Program. “Unfortunately, many doctors in the community still feel that way. But as a physician-scientist at the best cancer hospital in the country, I can’t just stand by. At MSK, we are making use of all the amazing resources we have to be able to understand and address this very complex problem.”

“Treating metastatic brain tumors is slowly turning into the last frontier in cancer care,” adds physician-scientist Viviane Tabar, Chair of MSK’s Department of Neurosurgery. “We often see people whose cancer is very well controlled in other parts of their body but who are still struggling with poorly controlled brain metastases.”

The symptoms of brain metastases and their impact can be severe. They may include headaches, nausea, weakness, seizures, and problems walking, speaking, and seeing.

An Increasing Problem in Cancer Care

“From a surgeon’s perspective, we are treating these tumors with a higher frequency than ever before, now that people have better options for medical treatment of their primary disease,” Dr. Tabar says.

There are no data to show that metastatic brain tumors are becoming more common, but there’s a general sense in the field that they are. One reason could be that better imaging techniques are more likely to detect tumors that have moved there. Another common opinion is that doctors are getting better at treating cancer in other locations so people are living longer and tumors have more time to grow in the brain.

Targeted drugs and other new therapies — such as EGFR and checkpoint inhibitors for lung cancer and HER2 inhibitors and hormone therapies for breast cancer — often are very effective at keeping cancer in check where it began. They can also work well in other organs where cancer has spread. But these therapies are less effective on tumors in the brain. This is due, in part, to what is called the blood-brain barrier. This barrier may make it harder for these drugs to reach the brain.

In addition, metastatic brain tumors usually are genetically very different from the original tumors. This is because cancer cells change as they grow and spread throughout the body.Back to top 

Identifying Variations in Tumor Biology

Because of these genetic differences, new approaches are needed to treat metastatic brain tumors. “We’re in a strange spot,” Dr. Boire says. “We know what the tumor used to be — a breast tumor, for example, or a melanoma tumor. And based on imaging, we know where it is. But we don’t know all the changes it’s gone through to get to where it is. That can be a challenge to figure out.”

To address this, MSK neurologists and pathologists are working together to develop liquid biopsies of the spinal fluid, which may contain DNA from brain tumors. This would allow them to run MSK-IMPACTTM, a test that simultaneously screens for hundreds of genes that drive tumor growth. Doctors can use it to determine the best targeted therapy for a tumor without having to obtain a tissue biopsy from the brain. “This would really be a game changer,” Dr. Boire notes.

Another tactic being studied by Dr. Boire and her colleagues, including Sloan Kettering Institute Director Joan Massagué, is finding drugs that target the microenvironment around the tumor, rather than the tumor itself. “There are many different kinds of cancer that can set up shop in the brain, which means it will be unlikely that we find one treatment that’s effective against all tumors,” she explains. “But there’s only one brain. Perhaps finding out how the brain responds to cancer holds the key to finding ways to treat brain metastasis.”

A Different Kind of Brain Tumor and Treatment

In addition to being different from the tumors in which they originated, metastatic brain cancers are also very different from primary brain cancers. Surgically, however, that may make these tumors easier to treat. “Compared with tumors like glioblastoma, brain metastases tend to look very different from the surrounding brain tissue. It is simpler to determine their boundaries when removing them,” Dr. Tabar explains. She adds that people who have surgery for brain metastases tend to recover very quickly. “Most patients can go home in only two or three days, and they usually do very well,” she says.

In some cases, brain metastases can occur in critical areas of the brain, such as those that control movement or speech. In those circumstances, Dr. Tabar doesn’t hesitate to use all of the surgical technology at her disposal. She might opt for brain mapping or keeping the patient awake during surgery. That way, she can “maximally protect their function,” she says. “Our aggressive approach to brain metastasis is motivated by the often excellent outcomes of surgery and radiation, and their positive impact on quality of life. There’s been enormous progress in systemic treatments, leading to improved survival.”

Many people with brain metastases have multiple tumors, not all of which can be removed with surgery. They are often treated with a combination of surgery and radiation. Several different types of radiation are available for people who require this treatment. These include intensity-modulated radiation therapy, which uses images from CT scans to focus high doses of radiation directly on the tumor; image-guided radiation therapy, which uses real-time imaging with a CT scan or x-rays during radiation therapy; and stereotactic radiosurgery, which can treat small tumors with a single high dose of radiation. These advanced technologies can focus the radiation beam at the specific area needing treatment while sparing the surrounding normal brain cells. Doctors at MSK avoid giving radiation to the entire brain to minimize side effects.

Radiation therapy and surgery are often combined for the same tumor, to minimize the chance it will regrow after surgery or if parts of it could not be removed. This may be the case if the tumor is in a key area of the brain or surrounding an important blood vessel. Radiation therapy may also be combined with immunotherapy.

A Multidisciplinary Team Focused on the Same Goal: The Individual

Another important contributor to MSK’s ability to treat metastatic brain cancer is our expertise in supportive services. “Our experts in rehabilitation, physical therapy, and other specialties make sure that our patients are strong enough to tolerate treatment,” Dr. Boire says. “We want to give everyone the best chance we can to have the best outcome possible after treatment is over.” This also includes experts in epilepsy, who are able to treat the seizures that are often caused by brain tumors.

“Metastatic brain cancer is a huge problem in oncology, and it doesn’t get the amount of attention it deserves,” Dr. Tabar concludes. “For that reason, here at MSK we are beginning to talk about building a formal center specifically for brain metastases. Assembling a group of experts on both the clinical side and in the lab will enable us to offer a multidisciplinary approach to a growing number of people who could benefit from an aggressive approach toward controlling brain metastasis.”

Experimental Cancer Drug Developed at MSK Leads to New Approach for Treating Alzheimer’s Disease

Source: Memorial Sloan Kettering - On Cancer
Date: 03/01/2018
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Like cancer, Alzheimer’s disease involves changes in proteins. When functioning normally, proteins are important for cells to work properly. Also like cancer, Alzheimer’s occurs more commonly in older people, reflecting the idea that it usually takes a long time for these kinds of cellular changes to build up to a point that they cause real damage.

So although it may be a bit surprising, it’s not an impossible stretch to think that a drug developed to treat cancer may also work against Alzheimer’s disease. A family of these drugs has its origins at Memorial Sloan Kettering.

MSK chemical biologist Gabriela Chiosis has developed compounds for both cancer and Alzheimer’s. This week she spoke about her work at the National Institutes of Health’s Alzheimer’s Disease Research Summit. Dr. Chiosis was among top researchers from around the world who were invited to present their research on the biology of Alzheimer’s.

“Of Dr. Chiosis’s many intriguing discoveries, one that stands out is that Alzheimer’s disease shares a common cellular abnormality with many cancers,” says Larry Norton, Deputy Physician-in-Chief for Breast Cancer Programs at MSK, who has collaborated with Dr. Chiosis on the development of drugs. “The fact that there is a common mechanism raises the possibility of a common therapy. So her research could have profound implications for many human diseases, particularly those associated with aging.”

Targeting the Disease Process

Dr. Chiosis’s current work is focused on a type of regulatory network found inside cells called epichaperomes. “Epichaperomes form under conditions of chronic stress, something that is found in both cancer and Alzheimer’s disease,” she says. “One of the roles of these networks is to enhance the processes that become disrupted in diseased cells. These processes include defective signaling, increased production of certain proteins, and inflammation.”

In 2005, Dr. Chiosis and her colleagues developed a drug called PU-H71 for the treatment of cancer. PU-H71 is now in a phase I/II trial for people with metastatic breast cancer. Based on their discoveries about PU-H71, she and her team later developed a related drug, which they called PU-AD, for Alzheimer’s disease.

Both drugs bind to a protein called Hsp90 but only when it’s incorporated into the epichaperome network. Hsp90 is a protein found in essentially every cell in the human body. Its normal role is to help with proper protein folding. But when it becomes part of the epichaperome, Hsp90 contributes to stabilizing the proteins inside cells that let the disease develop.

“The formation of the epichaperome keeps damaged cells alive while they remain dysfunctional,” Dr. Norton explains. “Dr. Chiosis’s discoveries about epichaperomes are important because they are so overarching and could apply to many diseases.”

Taking a Look Inside Cells

Dr. Chiosis’s research has also led to imaging methods for detecting epichaperomes in cancer and Alzheimer’s, called PU-PET and PU-AD PET, respectively. She has collaborated with other investigators at MSK, including radiochemists Jason Lewis and Naga Vara Kishore Pillarsetty and radiologists Mark Dunphy and Steven Larson, on their development.

The approach involves attaching a weak radioactive label to PU-H71 or PU-AD, which then can be imaged with PET scanning. For cancer, PU-PET allows doctors to identify who is most likely to benefit from PU-H71 treatment. It can also help doctors monitor how well the drug is working.

In her presentation at the NIH summit, Dr. Chiosis discussed how an understanding of the epichaperome network can be used to identify some of the changes that occur in a number of different pathways in brain cells. These pathways can lead to Alzheimer’s disease, and learning more about them could suggest possibilities for the development of new targeted drugs.

She also talked about how PU-AD PET can be used to visualize Alzheimer’s disease in the brain. “The negative effects on memory, behavior, and the ability to think clearly that are commonly witnessed in people with Alzheimer’s are due to accumulation of toxic proteins called amyloid and tau in the brain,” Dr. Chiosis says. “But toxic changes in the neuron may begin 20 years before these deposits or the clinical symptoms of the disease develop. As such, we believe that using PU-AD PET to detect Alzheimer’s during this long preclinical phase may provide a promising window of opportunity for treatment.”

Both the PU-PET and PU-AD PET scans are now being tested in clinical trials at MSK. Dr. Norton and Dr. Chiosis have established a company called Samus Therapeutics that is focused on developing these scans as well as new therapies that target the epichaperome.

New Classification System Will Improve Diagnosis and Treatment of Brain Tumors

Source: Memorial Sloan Kettering - On Cancer
Date: 03/14/2018
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There are more than 100 subtypes of brain tumors, making them a challenge to accurately diagnose. This week, an international team led by researchers at the German Cancer Research Center is announcing they have developed a new way to classify these tumors. A paper describing the tool was published in Nature.

Proper diagnosis and classification is vital for brain tumors. It not only helps with prognosis but also enables doctors to determine the best treatment. For example, some tumor types respond better to radiation therapy than others, while some respond to certain chemotherapy drugs. Some don’t need to be treated at all and can just be closely monitored.

We spoke with Memorial Sloan Kettering Pediatric Neuro-Oncology Service Chief Matthias Karajannis, who participated in the research, about why this study is important and what it means for people with brain cancer, both at MSK and around the world.

Why are brain tumors so hard to classify?

Brain tumors, especially in children, are not a uniform disease. They are actually many different diseases. Until recently, these tumors were diagnosed exclusively by looking at cells under a microscope. But even for the most experienced pathologist, it can be challenging to tell some of the different types apart. You could have three pathologists look at the same tumor sample and come up with three different diagnoses.

Advances in gene sequencing, such as MSK-IMPACTTM, have led to improvements. But there are limitations with sequencing cancer-related mutations, especially in pediatric brain tumors. Many of the subtypes don’t have a known gene mutation that is commonly linked with them that can be used to classify the subtype of tumor.

What’s different about the system that’s been developed now?

This research team has developed a completely new classification system. It is the first time anyone has shown a way to reliably distinguish from among the 100-plus different types of brain tumors.

The system looks at what is called the tumor’s methylation profile. Once the profile is determined in the lab, it can be fed into an algorithm in a computer and automatically matched with samples that already exist in the database. This approach is based on the fact that each tumor subtype has a different methylation profile.

Another aspect that was important about the study is that we demonstrated this approach is equally feasible and reliable across multiple cancer centers.

What is a “methylation profile”? How is it different from other types of tumor analysis?

Methylation is a way that DNA is modified without changing the sequence of the four DNA letters. It’s one of the factors that influences how and when genes are translated into proteins.

I like to use a music analogy. The DNA sequence is the notes on the page. The methylation profile helps determine how fast or slow the music is played, how loud or how soft.

When I came to MSK, I was pleased to learn that the Molecular Diagnostics Service, under the leadership of Service Chief Marc Ladanyi, was already establishing the technical platform to study the methylation profile of tumors. The equipment needed to do these kinds of studies had just arrived. Dr. Ladanyi and his team will be working with the New York State Department of Health to help methylation profiling become an approved clinical test, the first step toward insurance coverage. It’s currently considered an experimental test for research purposes.

Will this study affect how MSK diagnoses its patients?

We are already using this tool with all of our pediatric brain tumor patients, and with many adults who have brain tumors as well. We’ve been using it for a while. But now we’re in the process of working out an agreement with the German Cancer Research Center team so that we’ll be able to do all the analysis with the tool right here at MSK in Molecular Diagnostics. Currently, we send them the results from our methylation studies and they send back the information about tumor classification.

We are also looking at how methylation profiling can be used to diagnose other types of tumors, especially sarcomas. Sarcomas are another kind of tumor that have many, many different subtypes. And just like in brain tumors, these subtypes can be hard to distinguish based on how they look under the microscope, or even by looking at their genetic profile.

You came to MSK just over a year ago. Why did you decide to join the team?

I completed my fellowship training at MSK and then spent nine years at New York University School of Medicine. It was an exciting opportunity to return as Chief of the Pediatric Neuro-Oncology Service and to work with the world-renowned experts here, many of whom were part of my training.

MSK has one of the largest, if not the largest, pediatric neuro-oncology programs in the country. We see about 100 children who have been newly diagnosed with brain and spine tumors every year.

In addition, the research capabilities here are outstanding. Combining the infrastructure and equipment that was already here with my own work in molecular diagnostics made my coming here a perfect storm of opportunity. We are able to diagnose and treat people with brain cancer better than at any time before, and MSK is doing it better than any other institution.

What made you want to become a pediatric neuro-oncologist?

I went to medical school at a time when rapid progress was being made for treating other pediatric cancers, especially leukemia. There also were many new tools for diagnosing leukemia. By the time I graduated, the majority of children with blood cancers were being cured, thanks to better and more refined chemotherapy treatments.

I didn’t see the same progress being made for brain tumors. Techniques in surgery and radiation were getting better, and there was some limited success with chemotherapy. But there was still a lot of work to be done. Because I had lab training in molecular pathology, I knew that in the future, improving diagnosis would be a real game-changer in this field. And it has been. It’s been exciting and rewarding to be part of this quantum shift.

Salk team reveals clues into early development of autism spectrum disorder

Source: Salk Institute
Date: 01/07/2019
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Neurons from people with autism exhibit different patterns of growth and develop at a faster rate

Autism spectrum disorder (ASD) is a relatively common developmental disorder of communication and behavior that affects about 1 in 59 children in the US, according to the Centers for Disease Control and Prevention. Despite its prevalence, it is still unclear what causes the disease and what are the best ways to treat it.

Researchers at the Salk Institute compared stem cells created from individuals with ASD against stem cells created from those without ASD to uncover, for the first time, measurable differences in the patterns and speed of development in the ASD-derived cells.

The findings, published January 7, 2019, in the journal Nature Neuroscience, could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place.

“Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD,” says Salk Professor Rusty Gage, the study’s senior author and president of the Institute. “We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders.”

For the study, the researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells—cells that have the ability to develop into any cell type. They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors.

By using molecular “snapshots” from different developmental stages in the stem cells, the team was able to track genetic programs that switched on in a certain order as the stem cells developed into neurons. This revealed key differences in the cells derived from people with ASD. For instance, the Salk team observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD. This genetic program includes many genes that have been associated with higher chances of ASD. In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group.

“It’s currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred,” says first author Simon Schafer, a postdoctoral fellow in the Gage lab. “A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development.”

“This is a very exciting finding, and it encourages us to further refine our methodological framework to help advance our understanding of the early cell biological events that precede the onset of symptoms,” adds Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. “Studying system dynamics could maximize our chance of capturing relevant mechanistic disease states.”

The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression.

They next plan to focus on the creation of brain organoids, three-dimensional models of brain development in a dish that enable scientists to study the interactions between different types of brain cells.

“The current diagnostic methods are mostly subjective and occur after the emergence of behavioral abnormalities in young children,” Schafer says. “We hope these studies will serve as a framework for developing novel approaches for diagnosis during an early period of child development—long before behavioral symptoms manifest—to have the maximum impact on treatment and intervention.”

Other researchers on the paper were Apua C. M. Paquola, Shani Stern, Monique Pena, Thomas J. M. Kuret, Marvin Liyanage, Abed AlFatah Mansour, Baptiste N. Jaeger, Maria C. Marchetto and Jerome Mertens of Salk; David Gosselin of Université Laval in Quebec City, Canada; Manching Ku of the University of Freiburg in Freiburg, Germany; and Christopher K. Glass of the University of California San Diego.

This work was funded by The James S. McDonnell Foundation, G. Harold & Leila Y. Mathers Charitable Foundation, JPB Foundation, the March of Dimes Foundation, National Institutes of Health (NIH) grants MH095741 and MH090258, The Engman Foundation, Annette C. Merle-Smith, The Paul G. Allen Family Foundation, and The Leona M. and Harry B. Helmsley Charitable Trust. It was also supported by NIH grant P30 014195, the German Research Foundation (DFG) and the Chapman Foundation.

Research confirms nerve cells made from skin cells are a valid lab model for studying disease

Source: Salk Institute
Date: 01/15/2019
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Salk and Stanford team shows that induced neuronal cells derived from fibroblasts are similar to neurons in the brain, on the epigenomic level

The incidence of some neurological diseases—especially those related to aging, such as Alzheimer’s and Parkinson’s diseases—is increasing. To better understand these conditions and evaluate potential new treatments, researchers need accurate models that they can study in the lab.

Researchers from the Salk Institute, along with collaborators at Stanford University and Baylor College of Medicine, have shown that cells from mice that have been induced to grow into nerve cells using a previously published method have molecular signatures matching neurons that developed naturally in the brain.

The study, published in eLife on January 15, 2019, opens the door for better ways to model an individual patient’s disease. This technique would enable researchers to study how neurological conditions develop, as well as to test new therapies. The new technology also could help to advance research into gene therapies that are derived from a patient’s own cells.

“This research is charting the path for the most optimal way of creating neurons in the lab,” says Salk Professor Joseph Ecker, one of the study’s two senior authors. “By taking these cells and reprogramming them into neurons, you can potentially learn new things about how these diseases function on a cellular level, especially diseases driven by genetic changes.”

The cells used in the study, called fibroblasts, make up most of the connective tissue in animals and play an important role in wound healing. Researchers have been studying how to transform fibroblasts into neuron cells in laboratory dishes, but until now they didn’t know whether these newly created neurons accurately corresponded to neurons that had grown naturally in the brain.

The technique for inducing the fibroblasts to grow into neurons with the matching epigenome was developed by Stanford’s Marius Wernig, the paper’s co-senior author. With this method, making induced neuronal cells does not involve pluripotent intermediates. Instead, the cells are directly converted from fibroblasts to neurons.

“An important question in cellular engineering is how to know the quality of your product,” says co-first author Chongyuan Luo, a postdoctoral fellow in Ecker’s lab. “If we’re making neurons from fibroblasts, we want to know how they compare with neurons in the brain. We are particularly interested in looking at these cells at the level of the epigenome.”

The epigenome is made up of chemicals that attach to DNA and regulate when genes get turned on and translated into proteins. Differences between the epigenomes of induced and naturally grown neurons could result in different features of induced neurons that might make them less accurate models of neuronal behavior.

Using a technique developed in the Ecker lab called MethylC-seq, the researchers looked at every place in the genome where chemical groups called methyl groups are attached. They confirmed that these induced neurons have epigenomes that match neurons in the brain.

“This research was done in mouse cells, but we plan to use the same technology to study induced neurons made with human cells,” explains Ecker, who is director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. Ecker plans to also collaborate with colleagues to apply the technology to look at human cells to better understand age-related cognitive decline.

Other researchers on the paper were Rosa Castanon and Joseph R. Nery of Salk; Sean M. Cullen and Margaret A. Goodell of Baylor College of Medicine; and Qian Yi Lee, Orly L. Wapinski, Moritz Mall, Michael S. Kareta and Howard Y. Chang of Stanford.

The work was supported by the National Institutes of Health (grants P50-HG007735 and R01 DK092883), the California Institute for Regenerative Medicine (grant RB5-07466) and the Howard Hughes Medical Institute.

Novel technique helps explain why bright light keeps us awake

Source: Salk Institute
Date: 10/15/2019
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Researchers discover a way to make electron microscopy more detailed and precise by visualizing the activation of brain circuits over long distances

In recent decades, scientists have learned a great deal about how different neurons connect and send signals to each other. But it’s been difficult to trace the activity of individual nerve fibers known as axons, some of which can extend from the tip of the toe to the head. Understanding these connections is important for figuring out how the brain receives and responds to signals from other parts of the body.

Researchers at the Salk Institute and UC San Diego are reporting a novel technique for tracing these connections and determining how neurons communicate. The team used this technique to uncover details about how the brain responds to light signals received by the retina in mice, published October 15, 2019, in Cell Reports.

“This study is a breakthrough because no one could figure out how to study these connections before,” says Salk Professor Satchidananda Panda, co-corresponding author of the paper. “This new technique has enabled us to go well beyond the limitations of electron microscopy.”

The new method makes use of several different laboratory techniques to understand a type of neuron called intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells, which are found in the retina, in the back of the eye, express a protein called melanopsin that senses blue light.

The Salk and UCSD teams used a virus to deliver a protein called a mini-singlet oxygen-generating protein (mini-SOG) to the ipRGCs, so that the cells could be viewed in more detail under election microscopy. The system was designed to tether the mini-SOG to the membranes of the light-sensitive cells so that the entire neuron, including its long axons that reach out to different parts of the brain, can be easily tracked under both light and electron microscope.

“Thanks to development and application of new genetically introduced probes for correlated multiscale light and electron microscopic imaging, our Salk and UCSD-based research teams were able to follow the small processes emanating from nerve cells over centimeters, all the way from the retina to multiple places where they connect to brain regions critical to circadian rhythms, eye reflexes and vision,” says Mark Ellisman, distinguished professor of neurosciences at UC San Diego and adjunct professor at Salk, who co-led the work. “We were able to obtain unprecedented three-dimensional information about the machinery required for these neuronal cells to signal the next neurons in the complex circuits.”

Most of the previous work with mini-SOGs has been done in cell lines, and using them in mice, to map how neurons from the retina wire the brain, was a first, according the researchers. The method enabled them to glean new information about the connections between ipRGCs and different parts of the brain.

The ipRGCs are known to connect to many brain regions that regulate very different tasks. The cells tell one part of the brain how bright it is outside so that our pupil can rapidly close—in less than a second. The same ipRGCs also connect to the master clock in the brain that regulates our sleep-wake cycle. “However, it takes several minutes of bright light to make us fully awake,” Panda says. “How the same ipRGCs do these very different tasks with different time scales was not clear until now.”

The investigators found that the difference has to do with the way that light detected by the retina reaches the brain. By delivering the mini-SOG to the eyes of the mice, they were able to trace the signal to the part of the brain that constricts the pupil in response to light.

“These connections were much stronger—similar to water pouring out of a garden hose,” Panda says. “Whereas the connection between the ipRGCs and the master clocks were weaker—more like drip irrigation.” Because the ipRGCs deliver the light signal to the circadian center through this slower drip system, it takes longer for any meaningful information to reach and reset the brain clock.

“This research helps explain why, when you get up in the night to get a drink of water and turn on the light for a few seconds, you’re usually able to go right back to sleep,” Panda says. “But if you hear a noise outside and end up walking around your house for half an hour with the lights on, it’s much harder. There will be enough light signal reaching the master clock neurons in the brain that ultimately wakes up the rest of the brain.”

Panda says that the new technique will be useful for studying other neural connections, as the researchers can essentially use the same viruses to express mini-SOGs in any neuron and ask how different neurons make connections to different appendages.

“These findings and methods open new opportunities for brain researchers studying the long-distance wiring of brains in normal and in animal models of human disease,” adds Ellisman.

Other researchers on the paper were Luis Rios, Hiep Le, Yu Hsin Liu, Masatoshi Hirayama, Ludovic Mure, and Megumi Hatori of Salk and Keun-Young Kim, Alex Perez, Sébastien Phan, Eric Bushong, Thomas Deerinck, Maya Ellisman, Varda Lev-Ram, Suyeon Ju, Sneha Panda, Sanghee Yoon, and Mark Ellisman of the University of California at San Diego.

The research was supported by National Institutes of Health grants EY 016807, P41GM103412, RO1 GM086197, and RO1 NS027177.

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.

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.