New nuclear magnetic resonance technique offers ‘molecular window’ for live disease diagnosis

May 7, 2017

University of Toronto Scarborough researchers have developed a new “molecular window” technology based on nuclear magnetic resonance (NMR) that can look inside a living system to get a high-resolution profile of which specific molecules are present, and extract a full metabolic profile.

“Getting a sense of which molecules are in a tissue sample is important if you want to know if it’s cancerous, or if you want to know if certain environmental contaminants are harming cells inside the body,” says Professor Andre Simpson, who led research in developing the new technique.*

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An NMR spectrometer generates a powerful magnetic field that causes atomic nuclei to absorb and re-emit energy in distinct patterns, revealing a unique molecular signature — in this example: the chemical ethanol. (credit: adapted from the Bruker BioSpin “How NMR Works” video at http://www.theresonance.com/nmr-know-how)

Simpson says there’s great medical potential for this new technique, since it can be adapted to work on existing magnetic resonance imaging (MRI) systems found in hospitals. “It could have implications for disease diagnosis and a deeper understanding of how important biological processes work,” by targeting specific biomarker molecules that are unique to specific diseased tissue.

The new approach could detect these signatures without resorting to surgery and could determine, for example, whether a growth is cancerous or benign directly from the MRI alone.

The technique could also provide highly detailed information on how the brain works, revealing the actual chemicals involved in a particular response. “It could mark an important step in unraveling the biochemistry of the brain,” says Simpson.

Overcoming magnetic distortion

Until now, traditional NMR techniques haven’t been able to provide high-resolution profiles of living organisms because of magnetic distortions from the tissue itself.  Simpson and his team were able to overcome this problem by creating tiny communication channels based on “long-range dipole interactions” between molecules.

The next step for the research is to test it on human tissue samples, says Simpson. Since the technique detects all cellular metabolites (substances such as glucose) equally, there’s also potential for non-targeted discovery.

“Since you can see metabolites in a sample that you weren’t able to see before, you can now identify molecules that may indicate there’s a problem,” he explains. “You can then determine whether you need further testing or surgery. So the potential for this technique is truly exciting.”

The research results are published in the journal Angewandte Chemie.

* Simpson has been working on perfecting the technique for more than three years with colleagues at Bruker BioSpin, a scientific instruments company that specializes in developing NMR technology. The technique, called “in-phase intermolecular single quantum coherence” (IP-iSQC), is based on some unexpected scientific concepts that were discovered in 1995, which at the time were described as impossible and “crazed” by many researchers. The technique developed by Simpson and his team builds upon these early discoveries. The work was supported by Mark Krembil of the Krembil Foundation and the Natural Sciences Engineering Research Council of Canada (NSERC).


Abstract of In-Phase Ultra High-Resolution In Vivo NMR

Although current NMR techniques allow organisms to be studied in vivo, magnetic susceptibility distortions, which arise from inhomogeneous distributions of chemical moieties, prevent the acquisition of high-resolution NMR spectra. Intermolecular single quantum coherence (iSQC) is a technique that breaks the sample’s spatial isotropy to form long range dipolar couplings, which can be exploited to extract chemical shift information free of perturbations. While this approach holds vast potential, present practical limitations include radiation damping, relaxation losses, and non-phase sensitive data. Herein, these drawbacks are addressed, and a new technique termed in-phase iSQC (IP-iSQC) is introduced. When applied to a living system, high-resolution NMR spectra, nearly identical to a buffer extract, are obtained. The ability to look inside an organism and extract a high-resolution metabolic profile is profound and should find applications in fields in which metabolism or in vivo processes are of interest.

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Pre and post testing show reversal of memory loss from Alzheimer’s disease in 10 patients

June 28, 2016

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Results from quantitative MRI and neuropsychological testing show unprecedented improvements in ten patients with early Alzheimer’s disease (AD) or its precursors following treatment with a programmatic and personalized therapy. Results from an approach dubbed metabolic enhancement for neurodegeneration are now available online in the journal Aging.

The study, which comes jointly from the Buck Institute for Research on Aging and the UCLA Easton Laboratories for Neurodegenerative Disease Research, is the first to objectively show that memory loss in patients can be reversed, and improvement sustained, using a complex, 36-point therapeutic personalized program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.

“All of these patients had either well-defined mild cognitive impairment (MCI), subjective cognitive impairment (SCI) or had been diagnosed with AD before beginning the program,” said author Dale Bredesen, MD, a professor at the Buck Institute and professor at the Easton Laboratories for Neurodegenerative Disease Research at UCLA, who noted that patients who had had to discontinue work were able to return to work and those struggling at their jobs were able to improve their performance. “Follow up testing showed some of the patients going from abnormal to normal.”

One of the more striking cases involved a 66-year old professional man whose neuropsychological testing was compatible with a diagnoses of MCI and whose PET scan showed reduced glucose utilization indicative of AD. An MRI showed hippocampal volume at only the 17th percentile for his age. After 10 months on the protocol a follow-up MRI showed a dramatic increase of his hippocampal volume to the 75th percentile, with an associated absolute increase in volume of nearly 12 percent.

In another instance, a 69-year old professional man and entrepreneur, who was in the process of shutting down his business, went on the protocol after 11 years of progressive memory loss. After six months, his wife, co-workers and he noted improvement in memory. A life-long ability to add columns of numbers rapidly in his head returned and he reported an ability to remember his schedule and recognize faces at work. After 22 months on the protocol he returned for follow-up quantitative neuropsychological testing; results showed marked improvements in all categories with his long-term recall increasing from the 3rd to 84th percentile. He is expanding his business.

Another patient, a 49-year old woman who noted progressive difficulty with word finding and facial recognition went on the protocol after undergoing quantitative neuropsychological testing at a major university. She had been told she was in the early stages of cognitive decline and was therefore ineligible for an Alzheimer’s prevention program. After several months on the protocol she noted a clear improvement in recall, reading, navigating, vocabulary, mental clarity and facial recognition. Her foreign language ability had returned. Nine months after beginning the program she did a repeat of the neuropsychological testing at the same university site. She no longer showed evidence of cognitive decline.

All but one of the ten patients included in the study are at genetic risk for AD, carrying at least one copy of the APOE4 allele. Five of the patients carry two copies of APOE4 which gives them a 10-12 fold increased risk of developing AD. “We’re entering a new era,” said Bredesen. “The old advice was to avoid testing for APOE because there was nothing that could be done about it. Now we’re recommending that people find out their genetic status as early as possible so they can go on prevention.” Sixty-five percent of the Alzheimer’s cases in this country involve APOE4; with seven million people carrying two copies of the ApoE4 allele.

Bredesen’ s systems-based approach to reverse memory loss follows the abject failure of monotherapies designed to treat AD and the success of combination therapies to treat other chronic illnesses such as cardiovascular disease, cancer and HIV. Bredesen says decades of biomedical research, both in his and other labs, has revealed that an extensive network of molecular interactions is involved in AD pathogenesis, suggesting that a broader-based therapeutic approach may be more effective. “Imagine having a roof with 36 holes in it, and your drug patched one hole very well–the drug may have worked, a single ‘hole’ may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much,” Bredesen said. “We think addressing multiple targets within the molecular network may be additive, or even synergistic, and that such a combinatorial approach may enhance drug candidate performance, as well.”

While encouraged by the results of the study, Bredesen admits more needs to be done. “The magnitude of improvement in these ten patients is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective,” Bredesen said. “Even though we see the far-reaching implications of this success, we also realize that this is a very small study that needs to be replicated in larger numbers at various sites.” Plans for larger studies are underway.

Cognitive decline is often listed as the major concern of older adults. Already, Alzheimer’s disease affects approximately 5.4 million Americans and 30 million people globally. Without effective prevention and treatment, the prospects for the future are bleak. By 2050, it’s estimated that 160 million people globally will have the disease, including 13 million Americans, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer’s disease is on the rise–recent estimates suggest that AD has become the third leading cause of death in the United States behind cardiovascular disease and cancer.

Story Source:

The above post is reprinted from materials provided by Buck Institute for Research on Aging. Note: Materials may be edited for content and length.


Journal Reference:

  1. Dale E. Bredesen et al. Reversal of cognitive decline in Alzheimer’s disease. Aging, June 2016 [link]

https://www.sciencedaily.com/releases/2016/06/160616071933.htm

Scientists Can Read Your Mind Using These Images Of The Brain

May 16, 2015

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Scientists are now able to read people’s minds using MRI images of the brain that show specific patterns of neural activity.

In an experiment conducted by Carnegie Mellon University in Pennsylvania U.S., researchers deduced what people were thinking about by observing brain activity following a simple learning task.

Their study, funded by the US Office of Naval research, involved teaching a group of 16 people about the diet and habits of eight different animals and observing how they processed the new information.

the study participants learned about the habitat a

Using functional magnetic resonance imaging (fMRI), the scientists found that each person had a specific ‘brain activation signature’ — an indication of the neural activity — for the different animals.

So, each person had specific ‘habitat’ regions in the brain that stored new information about where the animals lived and dedicated ‘diet regions’ where the newly learned knowledge about animals’ diets was stored.

In this image ‘habitat’ brain regions are represented in green and ‘diet’ regions in red and blue.

mind reading

Since each animal invoked specific types of brain activity, scientists were able to use fMRI images and find out what animal each person was thinking about at any given time.

Describing the significance of the research Carnegie Mellon University stated that the program was in effect ‘reading their (participants) minds as they contemplated a brand-new thought.’

The wider implication of this is that scientists could one day use this method to look inside our minds and find out what type of objects we’re thinking about but based on this study alone, the method would only apply to objects such as houses, bananas or cars and not abstract thoughts.

The research, published in Human Brain Mapping, also revealed that animals that had shared diets or habitats gave rise to similar brain signatures.

Co-author and neuroscientist Marcel Just said: “The activation signature of a concept is a composite of the different types of knowledge of the concept that a person has stored, and each type of knowledge is stored in its own characteristic set of regions.”

Alongside the potentially scary thought of other people being able to read our minds, the study is also significant for learning about how the human brain processes new information.

Lead author Andrew Bauer explained:

“Each time we learn something, we permanently change our brains in a systematic way.

“It was exciting to see our study successfully implant the information about extinct animals into the expected locations in the brain’s filing system.”

Bauer and Just’s paper concluded that our brains all use a similar ‘filing system’ to process new information.

They claim their results will be able to help develop more effective ways of teaching complicated subjects in school as well as shed light on how to reverse the loss of knowledge that accompanies disorders such as Alzheimer and dementia.

http://www.huffingtonpost.co.uk/2015/06/10/scientists-can-read-the-human-mind-using-brain-activation-signatures-_n_7551102.html

A multifunctional medical nanoparticle

September 6, 2014

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“These are amazingly useful particles,” noted co-first author Yuanpei Li, a research faculty member in the Lam laboratory. “As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy) — all proven ways to destroy tumors.”

Researchers at UC Davis Comprehensive Cancer Center and other institutions have created biocompatible multitasking nanoparticles that could be used as contrast agents to light up tumors for MRI and PET scans or deliver chemo and other therapies to destroy tumors. The study was published online in Nature Communications.

“These are amazingly useful particles,” noted co-first author Yuanpei Li, a research faculty member in the Lam laboratory. “As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy) — all proven ways to destroy tumors.”

Jessica Tucker, program director of Drug and Gene Delivery and Devices at the National Institute of Biomedical Imaging and Bioengineering, which is part of the National Institutes of Health, said the approach outlined in the study has the ability to combine both imaging and therapeutic applications in a single platform, which has been difficult to achieve, especially in an organic, and therefore biocompatible, vehicle.

“This is especially valuable in cancer treatment, where targeted treatment to tumor cells, and the reduction of lethal effects in normal cells, is so critical,” she added.

These are not the first nanoparticles for medical use, but they may be the most versatile. Other particles are good at some tasks but not others. Non-organic particles, such as quantum dots or gold-based materials, work well as diagnostic tools but have safety issues. Organic probes are biocompatible and can deliver drugs but lack imaging or phototherapy applications.

Design of a multifunctional nanoparticle

The nanoparticles are built on a porphyrin/cholic acid polymer and are simple to make. Porphyrins are common organic compounds. Cholic acid is produced by the liver. The basic nanoparticles are 21 nanometers wide (a nanometer is one-billionth of a meter).

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers. At 32 nanometers, CNPs are ideally sized to penetrate tumors, accumulating among cancer cells while sparing healthy tissue.

In the study, the team tested the nanoparticles, both in vitro and in vivo, for a wide range of tasks:

  • CNPs effectively transported anti-cancer drugs, such as doxorubicin. Even when kept in blood for many hours, CNPs only released small amounts of the drug; however, when exposed to light or agents such as glutathione, they readily released their payloads.
  • The ability to precisely control chemotherapy release inside tumors could greatly reduce toxicity. CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.
  • CNPs can be configured to respond to light, producing singlet oxygen, reactive molecules that destroy tumor cells. They can also generate heat when hit with laser light. Significantly, CNPs can perform either task when exposed to a single wavelength of light.
  • CNPs combine imaging and therapeutics, simultaneously delivering treatment and monitoring treatment efficacy. They readily chelate imaging agents and can remain in the body for long periods. In animal studies, CNPs congregated in tumors, making them easier to read on an MRI. Because CNPs accumulated in tumors, and not so much in normal tissue, they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans.
  • “These particles can also be used as optical probes for image-guided surgery,” said Kit Lam of the Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis. “In addition, they can be used as highly potent photosensitizing agents for intraoperative phototherapy.”

The Lam lab and its collaborators plan to pursue preclinical studies and, if all goes well, proceed to human trials.

This research was funded by the National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, the Department of Defense, the Prostate Cancer Foundation, the Veterans Administration, and the California Institute for Regenerative Medicine.


Abstract of Nature Communications paper

Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise towards personalized nanomedicine. However, attaining consistently high performance of these functions in vivo in one single nanoconstruct remains extremely challenging. Here we demonstrate the use of one single polymer to develop a smart ‘all-in-one’ nanoporphyrin platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins can be used as amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI. Nanoporphyrins greatly increase the imaging sensitivity for tumour detection through background suppression in blood, as well as preferential accumulation and signal amplification in tumours. Nanoporphyrins also function as multiphase nanotransducers that can efficiently convert light to heat inside tumours for photothermal therapy (PTT), and light to singlet oxygen for photodynamic therapy (PDT). Furthermore, nanoporphyrins act as programmable releasing nanocarriers for targeted delivery of drugs or therapeutic radio-metals into tumours.

Self-assembling nanoparticle could improve MRI scanning for cancer diagnosis

July 16, 2014

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Scientists have designed a new self-assembling nanoparticle that targets tumours, to help doctors diagnose cancer earlier.

The new nanoparticle, developed by researchers at Imperial College London, boosts the effectiveness of Magnetic Resonance Imaging (MRI) scanning by specifically seeking out receptors that are found in cancerous cells.

The nanoparticle is coated with a special protein, which looks for specific signals given off by tumours, and when it finds a tumour it begins to interact with the cancerous cells. This interaction strips off the protein coating, causing the nanoparticle to self-assemble into a much larger particle so that it is more visible on the scan.

A new study published in the journal Angewandte Chemie, used cancer cells and mouse models to compare the effects of the self-assembling nanoparticle in MRI scanning against commonly used imaging agents and found that the nanoparticle produced a more powerful signal and created a clearer MRI image of the tumour.

The scientists say the nanoparticle increases the sensitivity of MRI scanning and will ultimately improve doctor’s ability to detect cancerous cells at much earlier stages of development.

Professor Nicholas Long from the Department of Chemistry at Imperial College London said the results show real promise for improving cancer diagnosis. “By improving the sensitivity of an MRI examination, our aim is to help doctors spot something that might be cancerous much more quickly. This would enable patients to receive effective treatment sooner, which would hopefully improve survival rates from cancer.”

“MRI scanners are found in nearly every hospital up and down the country and they are vital machines used every day to scan patients’ bodies and get to the bottom of what might be wrong. But we are aware that some doctors feel that even though MRI scanners are effective at spotting large tumours, they are perhaps not as good at detecting smaller tumours in the early stages,” added Professor Long.

The newly designed nanoparticle provides a tool to improve the sensitivity of MRI scanning, and the scientists are now working to enhance its effectiveness. Professor Long said: “We would like to improve the design to make it even easier for doctors to spot a tumour and for surgeons to then operate on it. We’re now trying to add an extra optical signal so that the nanoparticle would light up with a luminescent probe once it had found its target, so combined with the better MRI signal it will make it even easier to identify tumours.”

Before testing and injecting the non-toxic nanoparticle into mice, the scientists had to make sure that it would not become so big when it self-assembled that it would cause damage. They injected the nanoparticle into a saline solution inside a petri dish and monitored its growth over a four hour period. The nanoparticle grew from 100 to 800 nanometres — still small enough to not cause any harm.

The scientists are now improving the nanoparticle and hope to test their design in a human trial within the next three to five years.

Dr Juan Gallo from the Department of Surgery and Cancer at Imperial College London said: “We’re now looking at fine tuning the size of the final nanoparticle so that it is even smaller but still gives an enhanced MRI image. If it is too small the body will just secrete it out before imaging, but too big and it could be harmful to the body. Getting it just right is really important before moving to a human trial.”


Story Source:

The above story is based on materials provided by Imperial College London. The original article was written by Gail Wilson. Note: Materials may be edited for content and length.

MRI sensor allows neuroscientists to map neural activity with molecular precision

May 4, 2014
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This is the first time anyone has been able to map neural signals with high precision over large brain regions in living animals, offering a new window on brain function, says Jasanoff, who is also an associate member of MIT’s McGovern Institute for Brain Research.

Anne Trafton | MIT News Office

Launched in 2013, the national BRAIN Initiative aims to revolutionize our understanding of cognition by mapping the activity of every neuron in the human brain, revealing how brain circuits interact to create memories, learn new skills, and interpret the world around us.

Before that can happen, neuroscientists need new tools that will let them probe the brain more deeply and in greater detail, says Alan Jasanoff, an MIT associate professor of biological engineering. “There’s a general recognition that in order to understand the brain’s processes in comprehensive detail, we need ways to monitor neural function deep in the brain with spatial, temporal, and functional precision,” he says.

Jasanoff and colleagues have now taken a step toward that goal: They have established a technique that allows them to track neural communication in the brain over time, using magnetic resonance imaging (MRI) along with a specialized molecular sensor. This is the first time anyone has been able to map neural signals with high precision over large brain regions in living animals, offering a new window on brain function, says Jasanoff, who is also an associate member of MIT’s McGovern Institute for Brain Research.

His team used this molecular imaging approach, described in the May 1 online edition of Science, to study the neurotransmitter dopamine in a region called the ventral striatum, which is involved in motivation, reward, and reinforcement of behavior. In future studies, Jasanoff plans to combine dopamine imaging with functional MRI techniques that measure overall brain activity to gain a better understanding of how dopamine levels influence neural circuitry.

“We want to be able to relate dopamine signaling to other neural processes that are going on,” Jasanoff says. “We can look at different types of stimuli and try to understand what dopamine is doing in different brain regions and relate it to other measures of brain function.”

Tracking dopamine

Dopamine is one of many neurotransmitters that help neurons to communicate with each other over short distances. Much of the brain’s dopamine is produced by a structure called the ventral tegmental area (VTA). This dopamine travels through the mesolimbic pathway to the ventral striatum, where it combines with sensory information from other parts of the brain to reinforce behavior and help the brain learn new tasks and motor functions. This circuit also plays a major role in addiction.

To track dopamine’s role in neural communication, the researchers used an MRI sensor they had previously designed, consisting of an iron-containing protein that acts as a weak magnet. When the sensor binds to dopamine, its magnetic interactions with the surrounding tissue weaken, which dims the tissue’s MRI signal. This allows the researchers to see where in the brain dopamine is being released. The researchers also developed an algorithm that lets them calculate the precise amount of dopamine present in each fraction of a cubic millimeter of the ventral striatum.

After delivering the MRI sensor to the ventral striatum of rats, Jasanoff’s team electrically stimulated the mesolimbic pathway and was able to detect exactly where in the ventral striatum dopamine was released. An area known as the nucleus accumbens core, known to be one of the main targets of dopamine from the VTA, showed the highest levels. The researchers also saw that some dopamine is released in neighboring regions such as the ventral pallidum, which regulates motivation and emotions, and parts of the thalamus, which relays sensory and motor signals in the brain.

Each dopamine stimulation lasted for 16 seconds and the researchers took an MRI image every eight seconds, allowing them to track how dopamine levels changed as the neurotransmitter was released from cells and then disappeared. “We could divide up the map into different regions of interest and determine dynamics separately for each of those regions,” Jasanoff says.

He and his colleagues plan to build on this work by expanding their studies to other parts of the brain, including the areas most affected by Parkinson’s disease, which is caused by the death of dopamine-generating cells. Jasanoff’s lab is also working on sensors to track other neurotransmitters, allowing them to study interactions between neurotransmitters during different tasks.

The paper’s lead author is postdoc Taekwan Lee. Technical assistant Lili Cai and postdocs Victor Lelyveld and Aviad Hai also contributed to the research, which was funded by the National Institutes of Health and the Defense Advanced Research Projects Agency.

http://newsoffice.mit.edu/2014/delving-deep-into-the-brain-0501