Image post 8: mapping live brains

This image from UAB Research illustrates the improving brain maps that promise to reveal the mechanisms behind complex, neurological diseases.


























A MRI technology called diffusion tractography captured this image of a living rat brain. Tractography is a 3-D modeling technique that visually represents nerve pathways in the brain using data collected by diffusion tensor imaging (DTI).

DTI visualizes nerve pathways known collectively as white matter that connect the various parts of the brain via long bundles of nerve cells. It shows whether or not bundles of white matter fibers run in the same direction, but not in which direction. Tractography does that.

Since developed by researchers at Washington University School of Medicine in St. Louis, it has given the field a more detailed look at brain structures, especially living brains. Taken together, these new MRI technologies promise to improve understanding of neurological disorders like schizophrenia and Alzheimer's disease and the consequences of head trauma. They also may one day help neurosurgeons better avoid cutting nerves during surgeries.

In particular, tractography reveals connections that can be measured in living human subjects and measurements that can be made simultaneously across the entire brain. The Human Connectome Project is capitalizing on these strengths to build more accurate brain maps. The image was created in the lab of Hyunki Kim, Ph.D., associate professor in the departments of Radiology and Biomedical Engineering and faculty in the UAB Comprehensive Cancer Center.

Scratch-and-Sniff test for Parkinson's disease

Many of us grew up with iconic scratch-and-sniff technology. Maybe kids in your class had stickers that smelled like berries or popcorn when scratched. Mom's fashion magazine offered pungent samples of the latest perfume. According to its Wikipedia entry, everything from Nintendo video game packaging to a smell guide promoting the movie Spy Kids to Katy Perry's album Teenage Dream (cotton candy) have featured micro-fragrance coatings. Apparently, 3M came up with it by accident in the '60s during experiments on a copying technology.

Given the technology's pop-culture history, I was surprised to read a recent story in the Birmingham News that it is now being used to test people for early signs of Parkinson's disease. The story features video of David Standaert, M.D., Ph.D., chair of the Department of Neurology within the UAB School of Medicine, demonstrating the test. We asked him to talk about the science behind the test, as well as his team's involvement in a related study funded by the Michael J. Fox Foundation.



Show notes from the podcast: 

1:15 While the credit for the discovery of microfragrance coatings goes to 3M, it was the University of Pennsylvania that spent years developing the standard, scientific method for testing a person's ability to smell. Penn researchers must have had their reasons for including in the test certain smells -- dill pickle, grass, smoke, peach, turpentine, etc. -- but an explanation will have to wait for another post.

1:51 Researchers have known for years that people with Parkinson's disease lose their ability to smell, but not why. Neither did anyone make a connection between scratch-and-sniff technology and Parkinson's diagnosis for many years. Researchers first noticed the change because Parkinson's patients typically lose weight. Without the ability to smell, food loses it taste.

2:23  Old theories had it that Parkinson's disease, by interfering with muscle movement, meant that patients could not sniff as well. That idea was debunked by the work of German neuroanatomist Dr. Heiko Braak in 2003. His painstaking study revealed that among the first brain regions damaged as Parkinson's disease develops is the olfactory center.

4:07. People also lose their sense of smell after head trauma or exposure to harsh chemicals. This led to the major questions in the field like "what does it mean to lose your sense of smell?" and "can smell tests accurately reveal a change in the brain that points to pre-symptomatic, Parkinson's?" If you take a group of people who have lost the ability to smell and follow them through the years, what does that reveal?

4:40  The classic indicator that someone has Parkinson's disease is that their limbs begin to shake (tremor). In recent years it became clear that such a person's dopamine neurons have already lost about 70 percent of their function. An earlier warning sign is a must.

5:05 The damage of caused by Parkinson's to dopamine neurons probably starts a decade before hands start to tremble. Researchers once that the death of such nerve cells was the first thing to happen in the disease process, but not believe it happens in the middle.

6:10 So what happens first? Over the years, researchers had noted that people who would later go on to develop Parkinson's disease first suffered from a strange group of symptoms: sleeplessness, constipation and of course, loss of the ability to smell. With these symptoms so disparate, researchers did not realize for many years that they are influenced by buildup of the same protein, called alpha-synuclein, in the nervous systems of Parkinson's patients.

6:46 Those taking the Parkinson's sniff tests scratch a series of smell pads and answer questions about what they smell. Dr. Standaert's team tests people over 60 years of age, with thee expectation that about a third of them, if they have a sufficiently abnormal sense of smell based on a standard numerical score, will turn out to be in the early stages of Parkinson's disease. So if you are over 60 and can no longer smell normally, you have 66 percent chance of not having Parkinson's and a 33 percent chance of having it (up from 1 or 2 percent risk for the general population).

8:15 Another major thrust of the team's work is to study how nerve cells and nerve pathways that employ the major signaling chemical dopamine to pass on messages are different in people who have lost their sense of smell due to Parkinson's disease. It if turns out that people with with smell loss have a corresponding drop in dopamine function, the team will follow them over several years in hopes of revealing further details on early disease-causing mechanisms in Parkinson's disease.

11:00 Many labs are rigorously pursuing experimental drugs meant to slow the progression of Parkinson's disease. Should one or more of them be approved for use in the relatively near future, one can envision the creation of smell test screening programs for everyone as they turn 60. Those that do poorly, would then be referred for further testing, and preventive treatment could begin much earlier. In terms of a public health intervention, it would be relatively low cost because you could mass mail the sniff test cards with return postage, and people could mail them back in.

Those interested in more information or in participating in future trials should look up the Parkinson’s Progression Marker Initiative, or the Michael J. Fox Foundation survey. Those interested in local trials in Birmingham call also email Stephanie Guthrie at slguth@uab.edu.

Image post 5: eye nerves shed light on memory disorders

While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Below is a brief description of what we are looking at and how related work may contribute to a better understanding of Alzheimer's disease.

Pictured here is a retinal ganglion (center), a kind of nerve cell near the eye’s retina that helps to process light into the images we perceive. It had been injected with a fluorescent dye, which made it glow green along with the cells connected to it electrically. In each of our eyes, 125 million photoreceptors capture light. They then trigger nerve messages in 1.5 million retinal ganglion cells, long extensions of which bundle together to form the optic nerve.

Captured by Christianne Strang, Ph.D., research instructor in the Department of Vision Sciences within the UAB School of Optometry, this image represents signaling mechanisms between the retina and surrounding nerve cells. Strang's lab seeks to understand how photoreceptors connect to surrounding nerve pathways, as well as the degree to which they signal using the neurotransmitter acetylcholine.

Within nerve pathways, each nerve cell sends an electric pulse down an extension of itself called an axon until it reaches a synapse, a gap between itself and the next cell in line. When it reaches an axon’s end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Upon reaching the other side, they either cause the downstream nerve cell to “fire” and pass on the message, or stop the message. Certain neurological diseases, including Alzheimer’s, have been linked to a decrease in acetylcholine signals in nerve pathways related to vision and memory.

As for rest of the color scheme, the pictured eye tissue has also been treated with dyes that interact with choline acetyltransferase (blue), which helps to produce acetylcholine, and synaptophysin (red), which reveals the location of synapses. The work was done in the lab of Kent Keyser, Ph.D., professor in the School of Optometry.

Image post 1: brain message superhighways

While most posts from The Mix feature a science story, we also wanted a forum to share powerful images coming out of UAB research. Regular image posts will be accompanied by a brief description, including how the image depicted might soon be important to science or medicine. The post will also link to the creator of the image.

Above is a face view of a brain’s white matter created by UAB graduate student Meredith Reid using an MRI technology called diffusion tensor imaging (DTI). The strands running through the image are axons, long extensions of nerve cells that form pathways carrying messages between the parts of the brain. The colors represent the spatial orientation of the axons, with one color for those running left to right, another for those running back to front, etc. Certain qualities of such images give researchers a measure of the integrity of white matter axon fibers, which promises to improve understanding of neurological disorders like schizophrenia. The work was done in the lab of Adrienne Lahti, M.D., professor in the Department of Psychiatry and Behavioral Neurobiology within the UAB School of Medicine. On a final, related note, it's also worth checking out the Human Connectome Project run by the National Institutes of Health.  

Note: if you have an amazing UAB research image you would like to share, please email mwindsor@uab.edu.

Mind-blower: epigenetics makes memories

Do you remember your five-year-old birthday party? How about your wedding? Emerging science argues that you can do so because those experiences turned off genes at the time in a certain set of nerve cells in your brain. Stranger still, nerve cells may have this capability because they have re-purposed epigenetic mechanisms that other human cells use to "remember who they are."

To back up for a moment, epigenetic mechanisms are chemical changes that turn genes on and off without changing the genes encoded in DNA that we inherit from our parents. Research in recent years has established that they lend an extra layer of regulatory finesse to human genetics and make our complexity possible.

Epigenetics first made a splash in developmental biology. Researchers realized that while we have the same set of genes in every one of our cells, we develop 250 different cell types by the time we are born. Epigenetic mechanisms switch off a different set of genes (and leave a certain set on) in each cell type to result in the 250 types.

Stem cells that become bone or blood or liver cells as we develop "remember" their specialized nature, and they pass that memory on to their descendants as they divide and multiply in the constant turnover under way in most human organs.

This genetic memory is known to be accomplished by epigenetic mechanisms like methylation, the chemical attachment of a methyl group (one carbon and three hydrogens) to certain spots on the DNA chain. The process can turn surrounding genes off (prevent gene expression), while demethylation can turn them back on in an ongoing back and forth.

It really gets fascinating when you consider that the nerve cells making up the brain, unlike nearly every other human cell type, never divide and multiply, and so they never pass on genetic memory. One theory on this is that nerve cells have put their genetic memory mechanisms to another purpose: remembering.

Most of this is theoretical of course, and it is the subject of intense study in the lab of David Sweatt, Ph.D., chair of the UAB Department of Neurobiology and director of the Evelyn F. McKnight Brain Institute here. He sat down with The Mix to discuss his presentation at a recent UAB Epigenetics Symposium about how nerve cells may have evolved to store memories.




Show notes for the podcast:

1:47 Sweatt's lab explores the role of epigenetics in the adult human brain. That has required a re-definition of epigenetics, a science once thought pertinent only to cells that divide and multiply, and that pass on epigenetic marks to their descendants. Nerve cells in the brain do not divide, multiply or turn over as a population, and yet, epigenetics mechanisms are at work. The field now recognizes that such mechanisms contribute to learning and memory.

4:14 The genetics and epigenetics of inheritance has finally answered one of the most long-standing questions in human history: how are traits passed down from parents to children? Epigenetics in neurobiology is also answering another longstanding, philosophical question: What makes us who we are? It turns out that epigenetic mechanisms "sit at the interface" of nature (genes) and nurture (environmental factors make epigenetic mechanisms that turn genes on and off).

5:58 Epigenetics have provided for scientists a fundamental answer for how a single transient experience can make a permanent change in the biochemistry of the brain. It is no small thing that we are now beginning to understand this once-mysterious process.

8:10 Methylation is the mechanism that silences perhaps half or three-quarters of the genes in the human genome to make a nerve cell a nerve cell. Those changes are life-long, and so that set of silenced genes is the same in that family of cells for a lifetime.

12:02 A foundational discovery made in other labs in recent years is that epigenetic changes to nerve cells are necessary for humans to remember things for the long term. Once the field knew that, they could begin to try to understand the mechanisms.

12:35 If anyone who is listening to this podcast today remembers it tomorrow,  it will be because of changes in the genes being expressed in the nerve cells of their brains as they listen. There is a continuous, dynamic interplay between our experiences and the parts of our genes recording memories. Epigenetic mechanisms are powerful regulators of gene transcription and translation, and appear to have been applied by evolution to the problem of storing memories.

13:22 If evolving nerve cells could talk, they might have said, "OK, I have to control which genes are turned on and off in certain nerve cells to store memories, what is the toolbox I have at hand to accomplish this?" It's the same toolbox of epigenetic mechanisms it uses to control gene expression in general.

13:35 Methylation has been been mentioned as part of the toolbox. Then there is histone acetylation. DNA does not just float around in the nuclei of human cells, but is instead wrapped around protein "spools" called histones that help to organize, protect and regulate them as part of a larger package called chromatin. Part of DNA regulation is spatial, and works by controlling when certain parts of DNA chains are able to unravel from their spools. The unraveling makes a stretch of code accessible to the protein-making machinery. Attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible. In addition, there is phosphorylation and ubiquitination, processes that now appear to regulate both chromatin in general and behavioral memory formation.

14:51 With environmental factors (sunlight, smoking and pollution) known to make epigenetic changes, many labs are trying to determine whether such changes have roles in many diseases. Humans have a protective compartment surrounding their brains that screens out many toxins called the blood-brain barrier.

16:23 Sweatt's presentation at the UAB epigenetics symposium discussed how he is working to determine the exact biochemical mechanisms by which methylation is changing the firing patterns of nerve cells to endow networks of nerves with the ability to store memories. What are the exact and ongoing patterns of active methylation and demethylation as the brain reacts to sensory experiences?

18:00 To study the process of memory formation, Sweatt's lab examines certain classes of basic memories that we share, presumably, with study animals like mice. For instance, to survive, our animal ancestors would have had to be able to remember which places were dangerous and which offered food or security (spatial recognition of surroundings).

19:02 Humans appear to have "place cells" in our hippocampus, the part of the brain that tells you where you are and where you have been. When you walk into a new room, or even a new place in a room, a particular set of hippocampal neurons fires in certain patterns in such a way that allows the brain to record a 3D map of that place. Different cells fire when you are in different places. One experiment under way in Sweatt's lab is seeking to test whether certain DNA methylation patterns enable those cells to record that sense of place.

21:27 All this research is ultimately aimed at understanding the normal brain so as to come up with new treatments for those with disorders that affect memory (dementia, Alzheimer's, etc.) and learning. Sweatt's lab and many others are seek to build the framework for the development of new molecular targets for new kinds of drugs.

The previous three podcasts in this epigenetic series were Epigenetics has impact on health beyond DNA, Epigenetics, aging and cancer and Obesity, exercise and epigenetics: no excuses.

Dr. Sweatt’s research is largely funded by the McKnight Brain Research Foundation.

UAB team sets sights on neuroprotection

Neurological diseases are notoriously complex, and drugs have not improved significantly in decades. The main drug treatment for Parkinson's disease, L-DOPA, was first approved for use in 1970. It temporarily staves off symptoms but can itself cause heart arrhythmias, stomach bleeding and hallucinations. Patients with Parkinson's die at twice the rate of those without the disease.

For these reasons, researchers have been urgently seeking for years to understand Parkinson's to the point where they can begin to design drugs that go beyond symptom relief to counter the inflammation and nerve cell death at the disease's root. A team of researchers from the University of Alabama at Birmingham gave a presentation today at Neuroscience 2012, the annual meeting of the Society for Neuroscience in New Orleans,  in which they revealed that they may be approaching that point. The researchers have designed a set of experimental drugs called LRRK2 inhibitors that show evidence of protecting nerve cells, at least in the rodent and cell culture studies they have carried out so far, which are meant to approximate human disease.

But these are still just models, and therein lies the problem. Despite the excitement among researchers, when should patients begin to raise their expectations?

The UAB research team, and the field of neurology in general, is excited just to have identified an enzyme like LRRK2 against which they can design drugs that could reverse underlying disease processes. That would be a first for any neurodegenerative disease. Along with evidence that LRRK2 plays a crucial role in the mechanisms of Parkinson’s disease, it is the same kind of enzyme (although not the same one) that has been successfully targeted by existing cancer treatments, including Herceptin. On the other hand, the UAB team's LRRK2 inhibitors are still years away from human clinical trials. They must pass several basic tests (e.g. toxicology tests) before even being considered for human trials, and a great many drug candidates fail at this stage.

Perhaps the best we can do is to set down the facts, and offer just enough hope while avoiding hype.

The Mix sat down with Andrew West, Ph.D., associate professor in the Department of Neurology within the UAB School of Medicine, who gave the presentation today at Neuroscience 2012. We wanted his take on what has been accomplished so far, and on what lies ahead. Also please take a look at our related press release on his meeting presentation.


 
Show notes for the interview:

1:00 Patients are surprised to hear that there is today no treatment that reverses the underlying disease processes related to Parkinson's disease, and that the focus for decades has been on symptom relief only.

1:37 The other surprise facing newly diagnosed patients is that most of the treatments in use today were developed at least 50 years ago, so it's frustrating for them to learn about how limited their options are.

1:48 Traditionally, researchers have seen the death of nerve cells that make dopamine, the signaling chemical that contributes to our ability to control our movements, as the relentlessly progressive disease process underlying Parkinson's disease. This would explain how the disease, as it gets worse, eventually overwhelms older drugs that seek to relieve symptoms by replacing lost dopamine.

2:07  In recent years, however, the field has learned that although loss of dopaminergic neurons is important, disease processes may well affect pathways beyond dopamine.

2:48 In 2004, population studies found genetic mutations in the gene for an enzymne called LRRK2
in families at greater risk for an inherited form of late onset Parkinson's disease. The mutation most closely associated with the disease makes LRRK2 slightly over-active. The idea is to dial LRRK2 back with drugs.  The question still to be answered is whether or not LRRK2 represents a key controller of Parkinson's severity in all patients with the disease, including those that develop it for reasons unknown in their sixties.   

4:09  While there are still years to go before LRRK2 inhibitors could become available to patients, West says the field is further along in the process of developing a specific target to design drugs against than many Parkinson's researchers ever thought would happen.  

5:05 One of the challenges in neurodegenerative disorders is that humans may be the only creature to get certain diseases of the brain. And yet, to test whether an experimental drug is worthy of human trials, you need to try it first in animal models that mimic the human condition. West says the field is now making progress on creating such models, which may quicken the pace toward human studies. 

6:04  When it comes to developing drugs in the face of stricter regulations, industry and academia have learned in recent years to do more experiments on drug candidates early on, before research teams even apply for permission to start a clinical trial. West's team is repeating its experiments right now to be sure of its data, and to ensure that the team's would-be drug has strong effects in a model that mimics human disease. 

7:17  LRRK2 gets researchers excited because it is rare to find enzymes that are both proven to have a role in a disease of the brain, and that are structured such that a drug can change their action. LRRK2 is the same kind of enzyme (although not the same one) that has been safely and potently targeted by existing treatments for other diseases, including the cancer drugs Herceptin, Tarceva and Erbitux.

8:49 Inherited forms of disease can hide from evolution if they start late in life. They do not keep anyone from reproducing so there is no evolutionary pressure to weed them out of the gene pool.  

10:47 Researchers cannot differentiate between the symptoms of inherited Parkinson's disease linked to a LRRK2 mutation and symptoms in those who develop PD late in life for reasons unknown. That creates at least the possibility that LRRK2 may have a role in all of PD and that a drug fine-tuning LRRK2 could be helpful in all cases. West says he was shocked when it came to light that a disease as complicated as inherited Parkinson's could be caused by a mutation in a single gene.

12:00 Along with whatever is triggering Parkinson's disease, the idea has emerged in the field that the body's reaction to that trigger, the response of the immune system, may be making the disease worse by causing inflammation. LRRK2 may be a critical switch to deciding whether or not inflammation makes the disease worse. 

13:46 Getting a drug into clinical trials today requires a massive investment, so it does not pay to enter clinical trials prematurely. A rushed trial that fails because of poor design can result in a "black eye" for that drug target, making it harder to find funding for related research projects after that.  

15:22 West's team has been working with LRRK2 for several years now, and has been refining  proposed drug candidates that inhibit it. Their latest lead drug candidate overcomes many of the limitations of earlier generations of proposed drugs. It is capable of having its effect in the brain, and targets only LRRK2, and not any of the hundreds of enzymes it might interact with to cause side effects. 

16:32 West recommends that those interested in Parkinson's disease and related research look up the relevant webpage from the National Institute of Neurological Disorders and Stroke. Also very helpful are the websites for the Michael J. Fox Foundation, the Parkinson's Disease Foundation and the American Parkinson's Disease Association.