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.

DeepPET Uses Artificial Intelligence to Generate Images of the Body’s Internal Activities

Source: Memorial Sloan Kettering - On Cancer
Date: 04/19/2019
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Recently, the first-ever image of a black hole was splashed across front pages and filled up news feeds around the world. The image was made in part thanks to tremendous computing power that analyzed millions of gigabytes of data that had been collected from space.

Research that uses computer algorithms to create pictures from massive volumes of data is also going on at Memorial Sloan Kettering. Instead of probing the outer limits of the universe, this work seeks new ways to see what’s going on inside our bodies.

In a paper published in the May 2019 issue of Medical Image Analysis, MSK investigators led by medical physics researcher Ida Häggström report the details of a new method they developed for PET imaging. The system generates images more than 100 times faster than conventional techniques. The images are also of higher quality.

“Using deep learning, we trained our convolutional neural network to transform raw PET data into images,” Dr. Häggström says. “No one has done PET imaging in this way before.” Convolutional neural networks are computer systems that try to mimic how people see and learn what the important shapes and features in images are.

Deep learning is a type of artificial intelligence. In this technique, a computer system learns to recognize features in the training data and apply that knowledge to new, unseen data. This allows the system to solve tasks, such as classifying cancerous lesions, predicting treatment outcomes, or interpreting medical charts. The MSK researchers, including medical physicist Ross Schmidtlein and data scientist Thomas Fuchs, the study’s senior author, named their new technique DeepPET.

Peering into the Body’s Inner Workings

PET, short for positron-emission tomography, is one of several imaging technologies that have changed the diagnosis and treatment of cancer, as well as other diseases, over the past few decades. Other imaging technologies, such as CT and MRI, generate pictures of anatomical structures in the body. PET, on the other hand, allows doctors to see functional activity in cells.

The ability to see this activity is especially important for studying tumors, which tend to have dynamic metabolisms. PET uses biologically active molecules called tracers that can be detected by the PET scanner. Depending on which tracers are used, PET can image the uptake of glucose or cell growth in tissues, among other phenomena. Revealing this activity can help doctors distinguish between a rapidly growing tumor and a benign mass of cells.

PET is often used along with CT or MRI. The combination provides comprehensive information about a tumor’s location as well as its metabolic activity. Dr. Häggström says that if DeepPET can be developed for clinical use, it also could be combined with these other methods 

Improving on an Important Technique

There are drawbacks to PET as it’s currently performed. Processing the data and creating images can take a long time. Additionally, the images are not always clear. The researchers wanted to look for a better approach.

The team began by training the computer network using large amounts of PET data, along with the associated images. “We wanted the computer to learn how to use data to construct an image,” Dr. Häggström notes. The training used simulated scans of data that looked like images that may have come from a human body but were artificial.

The images from the new system were not only generated much faster than with current PET technologies but they were clearer as well.

Conventionally, PET images are generated through a repeating process where the current image estimate is gradually updated to match the measured data. In DeepPET, where the system has learned the PET scanner’s physical and statistical characteristics as well as how typical PET images look, no repeats are required. The image is generated by a single, fast computation.

Dr. Häggström’s team is currently getting the system ready for clinical testing. She notes that MSK is the ideal place to do this kind of research. “MSK has clinical data that we can use to test this system. We also have expert radiologists who can look at these images and interpret what they mean for a diagnosis.

“By combining that expertise with the state-of-the-art computational resources that are available here, we have a great opportunity to have a direct clinical impact,” she adds. “The gain we’ve seen in reconstruction speed and image quality should lead to more efficient image evaluation and more reliable diagnoses and treatment decisions, ultimately leading to improved care for our patients.”

Scientists Develop a Tool to Watch a Single Gene Being Transcribed in a Living Cell

Source: Memorial Sloan Kettering - On Cancer
Date: 07/05/2020
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A picture is worth a thousand words, or so the saying goes. But it can be quite a challenge to capture a picture of something that’s so tiny it’s on the scale of individual molecules.

The field of structural biology is dedicated to constructing images of very, very small things. But most of the techniques used by structural biologists to take these pictures require that the molecules are frozen in one position. This makes it difficult to watch the dynamic, shifting processes that are essential to life.

For the first time, researchers from the Sloan Kettering Institute have found a way to peer inside living cells and observe gene transcription. This is the process by which DNA is copied into messenger RNA (mRNA), which then specifies how a protein is made.

“Gene transcription is one of the most fundamental processes in all of biology,” says SKI structural biologist Alexandros Pertsinidis, senior author of the study, which was published in Cell. “We know that it’s highly regulated and uses complicated molecular machinery. Being able to watch this process as it happens is an important step forward in understanding what goes on inside cells.”

Following the Recipe

If you think of the genetic code as a universal cookbook, containing all of the instructions needed to make every part of a living organism, you can think of the various cell types as different restaurants, Dr. Pertsinidis explains. “French restaurants follow French recipes to make French dishes, and Italian restaurants follow Italian recipes to make Italian dishes,” he says. “In the same way, brain cells make the proteins that brain cells need to function, and liver cells make the proteins for liver function.”

A family of enzymes called RNA polymerases and a large set of factors that are associated with them regulate the transcription of individual genes and control the characteristics that cells exhibit. “The interplay between RNA polymerases and regulatory factors helps determine which genes are turned on and off in specific cells,” he says. “They also control how cells respond to outside signals, which can influence their activities.”

Until now, the function of RNA polymerases and associated regulatory factors has been studied indirectly, through biochemical reactions: Cells are broken open in a test tube and purified into individual parts. By adding or removing components and measuring the outcomes, scientists have been able to figure out certain molecular activities. How the machine as a whole works inside cells, however, has remained obscure.

“For 50 years, hundreds of researchers all over the world have studied these reactions,” Dr. Pertsinidis says. “But the problem has been that nobody has been able to directly observe how gene transcription happens inside a live cell.”

Zooming In on a Single Gene

In the study, the investigators used a highly specialized optical microscope to look at the activity of one RNA polymerase, called RNA polymerase II, as it interacted with genes and synthesized mRNA. The new method, developed by Dr. Pertsinidis’s lab, is called single-molecule nanoscopy.

To be able to look at the individual parts of cells, researchers label molecules with a fluorescent tag that makes them glow under the microscope. “But a cell is very crowded, and there are many reactions happening at the same time,” Dr. Pertsinidis says. “If you label all the polymerases in a cell, the whole nucleus is just a big glow.

“What’s new about this technology is the ultrasensitive, integrated system that lets us zoom in on a single tagged gene even when the cell nucleus is moving around and the specific chromosomal location is jiggling due to random microscopic motion,” he says. “At the same time, the system suppresses the signals from the other reactions that are happening, casting them into the background. This enables us to extract the signal for only the gene of interest and zoom in on it.”

The organization and dynamics of RNA polymerase II in the nucleus have been a topic of intense study over the past few decades. “Here, we directly observed the activity of this molecule and how it functions in the nucleus of live cells,” Dr. Pertsinidis says. “Being able to see how it interacts with other regulatory factors has unveiled the intricate hierarchies and interdependencies of these various factors. These insights enable us to reach a more detailed and comprehensive picture of transcription in live cells.”

Expanding to Other Cellular Processes

The researchers hope that their tool will be widely used to study complicated reactions inside living cells.

“There are enough details in our paper that other labs will be able to pick up and implement the technology,” Dr. Pertsinidis says. “We also have labs both inside and outside MSK that are interested in collaborating with us on specific projects.”

He adds that although he is focused on understanding gene transcription, the tools his team has developed could be used to study the details of other vital biological processes, such as DNA repair and protein synthesis.

Bull’s-Eye: Imaging Technology Could Confirm When a Drug Is Going to the Right Place

Source: Memorial Sloan Kettering - On Cancer
Date: 10/25/2019
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Targeted therapy has become an important player in the collection of treatments for cancer. But sometimes it’s difficult for doctors to determine whether a person’s tumor has the right target or how much of a drug is actually reaching it.

A multidisciplinary team of doctors and scientists from Memorial Sloan Kettering has discovered an innovative technique for noninvasively visualizing where a targeted therapy is going in the body. This method can also measure how much of it reaches the tumor. What makes this development even more exciting is that the drug they are studying employs an entirely new approach for stopping cancer growth. The work was published on October 24 in Cancer Cell.

“This paper reports on the culmination of almost 15 years of research,” says first author Naga Vara Kishore Pillarsetty, a radiochemist in the Department of Radiology. “Everything about this drug — from the concept to the clinical trials — was developed completely in-house at MSK.”

“Our research represents a new role for the field of radiology in drug development,” adds senior author Mark Dunphy, a nuclear medicine doctor. “It’s also a new way to provide precision oncology.”

Targeting a Unique Protein Network

The drug being studied, called PU-H71, was developed by the study’s co-senior author Gabriela Chiosis. Dr. Chiosis is a member of the Chemical Biology Program in the Sloan Kettering Institute. PU-H71 is being evaluated in clinical trials for breast cancer and lymphoma, and the early results are promising.

“We always hear about how DNA and RNA control a cell’s fate,” Dr. Pillarsetty says. “But ultimately it is proteins that carry out the functions that lead to cancer. Our drug is targeting a unique network of proteins that allow cancer cells to thrive.”

Most targeted therapies affect individual proteins. In contrast, PU-H71 targets something called the epichaperome. Discovered and named by Dr. Chiosis, the epichaperome is a communal network of proteins called chaperones.

Chaperone proteins help direct and coordinate activities in cells that are crucial to life, such as protein folding and assembly. The epichaperome, on the other hand, does not fold. It reorganizes the function of protein networks in cancer, which enables cancer cells to survive under stress.

Previous research from Dr. Chiosis and Monica Guzman of Weill Cornell Medicine provided details on how PU-H71 works. The drug targets a protein called the heat shock protein 90 (HSP90). When PU-H71 binds to HSP90 in normal cells, it rapidly exits. But when HSP90 is incorporated into the epichaperome, the PU-H71 molecule becomes lodged and exits more slowly. This phenomenon is called kinetic selectivity. It helps explain why the drug affects the epichaperome. It also explains why PU-H71 appears to have fewer side effects than other drugs aimed at HSP90.

At the same time, this means that PU-H71 works only in tumors where an epichaperome has formed. This circumstance led to the need for a diagnostic method to determine which tumors carry the epichaperome and, ultimately, who might benefit from PU-H71.

A New Way to Match Drugs to Tumors

In the Cancer Cell paper, the investigators report the development of a precision medicine tactic that uses a PET tracer with radioactive iodine. It is called [124I]-PU-H71 or PU-PET. PU-PET is the same molecule as PU-H71 except that it carries radioactive iodine instead of nonradioactive iodine. The radioactive version binds selectively to HSP90 within the epichaperome in the same way that the regular drug does. On a PET scan, PU-PET displays the location of the tumor or tumors that carry the epichaperome and therefore are likely to respond to the drug. Additionally, when it’s given along with PU-H71, PU-PET can confirm that the drug is reaching the tumor.

“This research fits into an area that is sometimes called theranostics or pharmacometrics,” Dr. Dunphy says. “We have found a very different way of selecting patients for targeted therapy.”

He explains that with traditional targeted therapies, a portion of a tumor is removed with a biopsy and then analyzed. Biopsies can be difficult to perform if the tumor is located deep in the body. Additionally, people with advanced disease that has spread to other parts of the body may have many tumors, and not all of them may be driven by the same proteins. “By using this imaging tool, we can noninvasively identify all the tumors that are likely to respond to the drug, and we can do it in a way that is much easier for patients,” Dr. Dunphy says.

The researchers explain that this type of imaging also allows them to determine the best dose for each person. For other targeted therapies, doctors look at how long a drug stays in the blood. “But that doesn’t tell you how much is getting to the tumor,” Dr. Pillarsetty says. “By using this imaging agent, we can actually quantify how much of the drug will reach the tumor and how long it will stay there.”

Plans for further clinical trials of PU-H71 are in the works. In addition, the technology reported in this paper may be applicable for similar drugs that also target the epichaperome.

This work was supported in part by National Institutes of Health grants (R01 CA172546, R56 AG061869, R01 CA155226, P01 CA186866, P30 CA08748, and P50 CA192937); William and Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Center for Experimental Therapeutics at MSK; and Samus Therapeutics.

MSK holds the intellectual rights to PU-H71 and [124I]-PU-H71. Gabriela Chiosis, Mark Dunphy, Steven Larson, Jason Lewis, Naga Vara Kishore Pillarsetty, Anna Rodina, Tony Taldone, and Pengrong Yan of MSK are inventors on the intellectual property, which MSK has licensed to Samus Therapeutics. As a result of this licensing arrangement, MSK has financial interests in Samus Therapeutics. Dr. Chiosis and co-author Larry Norton, Senior Vice President of MSK and Medical Director of the Evelyn H. Lauder Breast Center, have partial ownership in Samus Therapeutics and are members of its scientific advisory board, and Dr. Taldone has consulted for the company.