Tuesday, June 30, 2015

Unraveling the mysteries of the mitochondria in Huntington’s disease – and getting fast, clear, and useful results from research studies

In the collaborative quest for Huntington’s disease treatments, deepening affected families’ understanding of the key scientific challenges is vital. It can demystify the process of research, inspire involvement in investigative studies and clinical trials, and ultimately bolster the chances of defeating this horrible malady.

Noting the global nature of HD research, last month I highlighted key work on the West Coast of the United States. Andrew F. Leuchter, M.D., and Michael Levine, Ph.D., plan to measure brain energy waves to decipher the signals emitting from HD-affected individuals. Their work could ultimately lead to new drugs (click here to read more).

On the East Coast, at the Magnetic Resonance Research Center (MRRC) of the Yale School of Medicine, Doug Rothman, Ph.D., and his collaborators will conduct two unique studies that seek to unravel long-standing mysteries about Huntington’s and the mitochondria, the complex powerhouses of most of our cells.

“All the brain cells depend on them very heavily,” Dr. Rothman said during an interview at the MRRC on April 12.

Mitochondria came onto the evolutionary path about a billion years ago, he noted. They use oxygen to burn fuels (such as glucose, or common sugar) to provide energy for brain cells. In focusing on the mitochondria, Dr. Rothman’s studies aim to shed light on the serious energy deficits caused in HD and to provide tools for improving clinical trials.

As the Huntington’s community ramps up to a growing number of those trials, the paramount work of these scientists can help insure clear and useful results.

A mitochondrian (Wikipedia diagram by Mariana Ruiz Villarreal)

Novel and unique human studies

In people carrying the HD genetic abnormality, why do so many brain cells become damaged and eventually die, leading to HD symptoms? For decades, scientists researching this question mainly in animals and cell cultures have found much evidence implicating the mitochondria in the cells’ problems. However, they still don’t know exactly what the problem is.

Using the latest brain-scan technology, Dr. Rothman’s studies will involve human participants. They will focus on the mitochondria and the decline in cellular energy production, one of the main characteristics of HD.

“Anything that impairs the energy supply will severely impact brain function and will eventually impact cellular health,” Dr. Rothman said, adding that researchers suspect that mitochondrial dysfunction plays a part in many other neurological disorders.

Doug Rothman, Ph.D. (photo by Gene Veritas)

The first study seeks to identify a mitochondria-linked biomarker (a sign of disease or a disease mechanism) that could lead to a faster, more efficient way of testing potential HD remedies. The second aims to answer a major question: are less active mitochondria a cause or an effect of the disease?

“There’s lots of preclinical studies that suggest mitochondrial alterations,” Dr. Rothman said, referring to animal studies. “What’s nice is that the MR [magnetic resonance] technology allows this aspect of mitochondrial function to be measured non-invasively in vivo.”

These studies are “novel” and “unique” because they will involve “patients who have the gene,” he added. “Before it would have to be done on a preclinical model. There was no way to directly study humans until the development of the MR technology.”

Described below, the specific types of MR scans in Dr. Rothman’s studies will be used on HD-affected individuals for the first time, he said.

Pioneering the technology

Dr. Rothman helped pioneer this technology. It is recognizable to most people in the form of the MRI scanners that became common in medical diagnostics worldwide over the past two decades.

In working toward his Ph.D. at Yale, received in 1987, Dr. Rothman specialized in a technique known as NMR, nuclear magnetic resonance.  When used in humans NMR is now referred to as MRS, magnetic resonance spectroscopy. He and other specialists have applied MRS to the study of disease. In 1989 he was appointed to the Yale Medical School faculty, and in 1995 he became the director of the Magnetic Resonance Research Center.

As researchers refine these techniques, they have become ever more capable of picking up the resonance – literally a radio frequency – of the chemicals that make up living organisms, including humans.

In both MRS and the more familiar MRI, radio pulses are given to subjects inside huge magnets.  The radio pulses excite (stimulate) chemicals in the body while a person lies in the machine, analogous to a bell being struck. Each compound then resonates (again analogous to a bell) at a characteristic radio frequency. By measuring the radio signal from the different resonating chemicals the chemical composition of different brain regions can be determined.

Dr. Rothman stressed that the technology is safe. “You’re not exposed to any radiation at all – literally just radio frequency,” he said of the scanners, which detect the radio frequencies coming out of the body.

“You literally could set up an FM radio and pick these up,” he continued. “Really, the system’s main difference from a standard radio is just the sensitivity and stability, because we’re talking about very small differences of frequency, as opposed to say a megahertz, as you have in FM radio.”

The scanner sends the readings to a computer for analysis.

Understanding brain metabolism

Using MRS, Dr. Rothman and his colleagues at the MRRC contributed to breakthroughs in understanding the biochemistry of type 2 diabetes. He also helped make important discoveries about the biochemistry of the liver and muscles.

At the same time, he and others discovered ways to measure levels of chemicals in the brain. Those chemicals included metabolites, which provide energy, and neurotransmitters, which are involved in signaling between brain cells.

For the first time in human brain scans, Dr. Rothman and his colleagues detected key chemicals such as ethanol and glucose. They also saw the major neurotransmitters glutamate and GABA (gamma aminobutryric acid), substances mentioned frequently in the world of HD research.

This group of scientists made other important advances in the understanding of brain metabolism. Of particular potential importance for HD, they discovered the energy cost for supporting brain glutamate and GABA neurotransmitter activity, providing a direct link between mitochondrial health and brain function.

As a result of their discoveries, Dr. Rothman and a group of colleagues saw how levels of glutamate and GABA are altered in depression, epilepsy, and other psychiatric disorders, and how drugs can impact those levels.

Dysfunction seen in animals

Several years ago, Dr. Rothman added Huntington’s disease to his focus. Funded by CHDI Foundation, Inc., the multi-million-dollar nonprofit virtual biotech dedicated to finding HD treatments, Dr. Rothman and his lab staff conducted research on mitochondria and brain cell metabolism in two types of transgenic HD mice.

Using MRS scans, in both groups of mice the team found a decline in metabolism in three key regions of the brain (cortex, thalamus, and striatum). They also discovered a reduction in brain cell glutamate and GABA signaling activity.

“The changes were much more profound as the models reached the late premanifest or manifest stage,” Dr. Rothman said during a presentation of the research in February at the CHDI-sponsored 10th Annual HD Therapeutics Conference.

These findings suggested that mitochondrial dysfunction plays a role in HD. This and his upcoming studies are part of a larger group of biomarker studies necessitated by the advent of clinical trials.

You can watch Dr. Rothman’s presentation in the video below.

High-powered brain scans

With CHDI support, Dr. Rothman hopes to carry out the human studies in the second half of this year.

Each study will require about 40 volunteers: 20 early-stage HD-affected individuals and 20 gene-negative volunteers to act as a comparison group. Each study will involve a brain scan and take two or three days, including travel time. The study will cover the cost of travel, food, and lodging. Volunteers can take part in both studies, if they wish.

In the first study participants will undergo a so-called proton scan lasting 60-90 minutes. The Rothman team will use Yale’s 7 Tesla scanner. The number of Teslas corresponds to the power of the magnet, with higher Tesla giving greater sensitivity (the ringing discussed above has a higher amplitude and frequency).

“Seven Tesla is about the highest magnetic field that can be used for human studies,” said Dr. Rothman. “Your molecules move around and jitter and release a radio signal that interferes with the measurement, and so we need as about as high a sensitivity as possible. Interestingly, within a chemical, the protons all have different frequencies. So you can actually identify a chemical based on the pattern of resonance frequencies.”

At this level, the scientists can measure more types of metabolites and with greater sensitivity, allowing them to distinguish between glutamate and another neurotransmitter, glutamine. Both are involved in a cycle involving GABA, brain cell signaling, and metabolism. The research team aims to determine whether glutamine or glutamate is most altered by the disease.

Yale's 7 Tesla scanner (photo by Gene Veritas)

Optimizing treatments

The researchers will focus primarily on glutamine, because it is the most sensitive chemical marker in the brain, but it’s not easily measured in humans at 3 Tesla or lower (scanners with less sensitivity), Dr. Rothman explained.

The more sensitive the biomarker, the better the chance of measuring the effects of the disease and potential treatments, he added.

This biological fine-tuning raises the possibility of studying the disease and testing therapies in small groups, perhaps even single subjects – a far more efficient, inexpensive, and faster way to treatments than the traditional, larger studies involving dozens or scores of individuals.

“The hope is that it would be possible to get immediate feedback before any behavioral-motor changes and use that to optimize individual subjects’ therapy,” Dr. Rothman elaborated.

Tracing the journey of sugar

In the second study Dr. Rothman will use 13C (carbon-13) MRS, the same technique used in the HD-mouse mitochondria project (discussed above) and in human scans for a variety of conditions. Carbon-13 is a natural, stable isotope that makes up about 1.1 percent of all the carbon on earth. Researchers use it to label substances so they can be tracked through the body.

Participants will lie in a 4 Tesla scanner for about two hours. They will be continuously injected with 13C-labeled glucose through a catheter in one arm. From a catheter in the other arm small blood samples will be taken to read levels of 13C and glucose. Glucose is used because it is the main fuel that the mitochondria burn to provide the brain with energy.

Lab assistants will monitor participants’ glucose levels to make sure they remain stable. Afterwards, the participants will receive orange juice and lunch in a standard recovery room, where assistants will make sure that their glucose levels have returned to normal.

As Dr. Rothman explained, the 13C MRS technique will allow his team to watch the glucose go through the various stages of the energy cycle in the brain. This metabolic process includes the transformation of glucose into lactate, then into glutamate by way of what is known as the TCA (tricarboxylic acid) cycle in mitochondria. The rate of flow of glucose into the mitochondria is proportional to the amount of energy the mitochondria produce.

“We can also measure the flow from glutamate to glutamine, which gives us the rate of glutamate neurotransmission, a direct measure of brain function,” he added.

As a result, the team can measure the rate of energy production in individual brain cells, as well as the rate of brain signaling (neurotransmission).

Dr. Rothman summarized: “We have a measure of both the energetics of the neuron – how much energy is the mitochondria making – and a measure of the function of the neuron – how much it’s signaling, how much glutamate it’s releasing through the flow into glutamine.”

The team will attempt to answer two questions: whether energy production decreases in early-stage HD individuals, and, if so, whether the drop results from impairments in the mitochondria.

Based on animal studies and previous human studies using other techniques, Dr. Rothman and his team believe they will find diminished energy production in the mitochondria.

“But that doesn’t, by itself, tell us that the mitochondria are causing it,” he said. “It could be many other things.”

Dr. Rothman making an adjustment on Yale's 4 Tesla scanner (above) and standing the in recovery room where 13C study volunteers will have glucose readings monitored afterwards (below) (photos by Gene Veritas)

Verifying the impairment

The 13C experiment will examine the rate of energy production of the mitochondria. To further tease out the questions about the role of the mitochondria in HD, Dr. Rothman and his team want to measure the demand on the mitochondria for energy production. 

To do so, they will run a second experiment during the 13C scans. Using phosphorous magnetic resonance spectroscopy, they will analyze the level of other compounds used for brain cell energy. Specifically, they will measure the synthesis of ATP (adenosine triphosphate) from ADP (adenosine diphosphate) (click here to learn about this process). The breakdown of ATP back into ADP by the mitochondria releases energy to fuel cellular processes, he said.

“In the muscle it fuels contraction,” Dr. Rothman said. “In the brain it fuels neurotransmission. If the mitochondria have a defect or have a low number or activity, they have to be driven harder for the same amount of energy production.”

For this measurement to occur, the participants must have their brains stimulated. “So both people with HD and control subjects will be given visual scenes in the magnet that will force the visual cortex we’re measuring to be active,” Dr. Rothman explained.

If the HD subjects have a mitochondrial impairment, the team will be able to determine whether the mitochondria “are being forced to work harder, because their capacity is less,” he said.

In combination with the 13C MRS readings, this experiment will help the scientists conclude whether “the problem is at the mitochondria,” Dr. Rothman said. This knowledge will help in the design of potential remedies and the clinical trials to test them.

The 13C study will measure energetics and signaling, as shown in this rendition of the glutamatergic synapse (image courtesy of Dr. Rothman)

Gratitude for the scientists’ work

Dr. Rothman said he expects the proton study to take about 18 months and the 13C study about 24 months. Once the studies commence, a call for volunteers will go out from the MRRC. If recruitment goes well, the studies may finish sooner, he said.

Upon the completion of the proton study, CHDI will evaluate the feasibility of glutamine as a treatment biomarker in comparison with glutamate and other MRS biomarkers under study, he added. Later Dr. Rothman’s team will file a report on the studies with CHDI, and they aim to submit their work to a scientific journal.

The engagement of Dr. Rothman and Yale Medical School in HD science exemplifies the seriousness of CHDI and HD researchers in the quest for treatments.

With the goal of unraveling the mysteries of the mitochondria, Dr. Rothman’s experiments can potentially complete key parts of the HD treatment puzzle. The search for effective biomarkers and increased knowledge about the role of the mitochondria can speed the movement of discoveries from scientific bench to patient’s bedside.

As a Yale graduate and carrier of the HD genetic defect, I was especially thrilled to interview Dr. Rothman. My alma mater may very well be helping to save me and thousands of others from the ravages of HD.

I am grateful each day for the commitment of Dr. Rothman and scientists around the globe to defeat HD.

Gene Veritas (aka Kenneth P. Serbin) at Yale University in New Haven, CT, April 2015 (photo by Gene Veritas)

Friday, May 29, 2015

Overcoming the Fear of the Lion: A Courageous Film About Genetic Testing and Huntington's Disease

A new documentary, The Lion’s Mouth Opens, poignantly captures the precarious journey into genetic self-knowledge by Marianna Palka, a 33-year-old filmmaker-actress. She has decided to test for Huntington's disease (HD), which has been referred to as the "devil of all diseases."

The film premieres on HBO on June 1 at 9 p.m. ET.

Read my preview of the film in The Huffington Post.

Wednesday, May 20, 2015

The search for Huntington's disease treatments is indeed ‘rocket science’ – and we can all help build the rocket

For people facing Huntington’s disease and other devastating, untreatable conditions, the powerful wish for a cure can conjure up the image of an elated scientist bursting from a laboratory and declaring “Eureka!”

However, it is unlikely a treatment for HD will emerge in this way.

We often misunderstand scientific progress, as explained in an essay in the May 16, 2015, edition of The New York Times by prominent physicist Leonard Mlodinow, Ph.D.

“Why do we reduce great discoveries to epiphany myths?” asked the sub-headline for Dr. Mlodinow’s online article, which was titled “It Is, in Fact, Rocket Science.”

“The mythical stories we tell about our heroes are always more romantic and often more palatable than the truth,” Dr. Mlodinow writes. “But in science, at least, they are destructive, in that they promote false conceptions of the evolution of scientific thought.”

From Isaac Newton to Charles Darwin to Stephen Hawking, we have oversimplified the process of discovery, Dr. Mlodinow explains. Rather than the eureka moments popularized in books and the media – like the apple falling on Newton’s head – these scientists’ discoveries involved years of hard work and questioning of assumptions, including their own.

Thus, Dr. Mlodinow reminds us that breakthroughs result from the cumulative build-up of many moments of discovery by scientists past and present.

He thus underscores a crucial point for the Huntington’s disease community: finding treatments will necessarily involve a collective effort by scientists and volunteers in research studies and clinical trials.

“Even if we are not scientists, every day we are challenged to make judgments and decisions about technical matters like vaccinations, financial investments, diet supplements and, of course, global warming,” Dr. Mlodinow points out. “The myths can seduce one into believing there is an easier path, one that doesn’t require such hard work.”

We in the HD community must all play our part in the quest for treatments.

A eureka moment deflated

As a carrier of the deadly HD mutation who watched his mother succumb to the disease, I have sometimes fallen prey to the seductive scenario described by Dr. Mlodinow, and even done so in this blog.

Four years ago this month, I was so excited about Alnylam Pharmaceuticals’ progress towards a remedy that I posted a picture of myself holding an Alnylam compound designed to attack HD at its genetic roots. I wrote that the compound, “the potential cure in my hand,” seemed magical.

I later made the image my Facebook profile photo.

(See the photo below and click here to read more.)

Gene Veritas holding the Alnylam compound in 2011 (photo by Dr. Matthias Kretschmer, Alnylam)

I had perhaps become overconfident about the Alnylam project.

In collaboration with its partners Medtronic and CHDI Foundation, Inc., the nonprofit virtual biotech focused on HD treatments, Alnylam was planning to apply in 2012 for permission to start a clinical trial.

In early 2012, however, Alnylam cut a third of its work force in order to reduce costs. In May of that year, less than a year after my 2011 visit, the company shifted its business strategy. It downgraded the HD project and fired the scientific director in charge

Alnylam chose instead to concentrate on less complex – and perhaps more profitable – projects to find drugs for other conditions. Alnylam passed on the responsibility for testing the compound in a human clinical trial to Medtronic.

To date, Medtronic has announced no plans for a human clinical trial of the Alnylam compound.

“Medtronic believes the siRNA [gene-silencing] drug-device program continues to represent an exciting opportunity to combine an innovative therapeutic strategy with state-of-the-art drug device delivery technology for Huntington’s disease,” Jack Lemmon, Ph.D., a Medtronic program manager, responded in an e-mail to my request for an update on the project. “Pre-clinical work has generated promising results; however the therapy research program has been paused since 2013 until partnerships can be established allowing us to sustain the research. At this time, it is premature to discuss timeframes, but we hope to continue work to find a treatment for this devastating neurodegenerative disease.”

Shots on goal

I am concerned that the project runs the risk of entering a not uncommon limbo, which one former director of the National Institutes of Health calls the “valley of death,” the increasingly difficult transition between laboratories and clinical trials.

Devising the Alnylam compound involved a significant investment of time, money, and expertise. In my extensive interviews with Alnylam scientists in 2011, and even in a conference call with some of those same researchers after the announcement of the 2012 cutback, they expressed enthusiasm about the promise of the compound.

The Alnylam compound may – or may not – ultimately play a role in the search for treatments.

Without the Alnylam compound, the HD community would have one less shot on goal in the critical gene-silencing field.

I am disappointed at the lack of action – much less progress – regarding the Alnylam compound.

Fortunately for the HD community, one of those shots is scheduled to take place this year: Isis Pharmaceuticals, Inc., and Roche will start a historic gene-silencing clinical trial using a different type of drug technology. Other companies and labs are also focusing on the development of gene-silencing approaches for HD.

The Alnylam project didn’t meet the expectations of many in the community. However, it has still provided valuable data from which other researchers can benefit. I am grateful for Alnylam’s contributions to the quest for treatments, and I’m crossing my fingers that Medtronic can resume the project.

I indeed recognize that the path to treatments is not easy. Nor is it straight.

One example of a potentially fortuitous outcome of the Alnylam decision: the dismissed HD project director, Dinah Sah, Ph.D., now works as the senior vice president of neuroscience for Voyager Therapeutics, one of the new companies exploring gene-silencing for HD.

Dinah Sah, Ph.D., of Voyager Therapeutics (photo by Gene Veritas)

A road paved with cooperation

Enthusiasm is essential, but it must be tempered with the recognition that scientists need time – and money – to test hypotheses.

It took some two decades to discover the huntingtin gene. At the time of this breakthrough in 1993, people in the HD community celebrated.

Rightfully so, hope for treatments increased significantly.

Since then, hundreds of researchers from around the globe have published thousands of scientific papers on HD. Along the way they have identified hundreds of potential HD drug targets (biological pathways).

From the 1970s until today, thousands of individuals from HD-affected families have participated in research studies and, more recently, a growing number of clinical trials.

While many of us are disappointed that successful treatments have not emerged, we must recognize that the enormous amount of scientific work regarding HD should contribute – perhaps in ways no one yet knows – to future progress.

The road to treatments is paved with cooperation, and with the recognition that multiple drugs may be needed to manage this complex genetic disorder. (Thus, scientists don’t say “cure” when referring to HD.)

Cooperation: the HD community out in force at an HDSA Team Hope Walk (photo by Gene Veritas)

Something larger than ourselves

Our society worships individual “heroes.

However, in the fight to defeat HD, each participant contributes with his or her talents and resources: financial donations, scientific expertise, caregiving, and daily dedication to the cause.

In this long-term commitment, we strive for the well-being of those beyond ourselves: the children who have yet to develop symptoms, the future generations of HD families, and other disease communities such as Alzheimer’s, Parkinson’s, and many conditions even rarer than HD like dentatorubral-pallidoluysian atrophy, known as DRPLA.

For now, I’ll keep my Facebook profile photo as a symbol of hope governed by caution.

Yes, defeating HD is rocket science. When, collectively, we have completed that rocket, we can all ride it together.

(Please remember during HD Awareness Month to donate generously to the Huntington’s Disease Society of America or the HD cause of your choice!)

Sunday, May 10, 2015

Deciphering signals from Huntington’s disease brains in the search for treatments

From coast to coast and around the world, scientists like Andrew F. Leuchter, M.D., and Michael Levine, Ph.D., are engaged in the quest for Huntington’s disease treatments.

During May, Huntington’s Disease Awareness Month, I want to call attention to the critical work of Drs. Leuchter and Levine on the West Coast. They exemplify the partnership of scientists and physicians with the HD community, aiming to advance potential remedies into crucial clinical trials.

Drs. Leuchter and Levine, faculty researchers at the renowned Semel Institute for Neuroscience and Behavior at the University of California, Los Angeles (UCLA), are collaborating on a project that could ultimately lead to new drugs. In the near term, they aim to understand more fully the electrical signals that naturally but abnormally emanate from the brains of HD patients and presymptomatic carriers of the HD gene mutation like me.

“Most of the brain’s energy goes to creating electrical gradients – electrical impulses – but we haven’t been very good at using that for diagnosis and treatment,” Dr. Leuchter said during a March 20 interview in his office at the Semel Institute. He and Dr. Levine aim to “decipher the signals that are coming out of the brain.”

The Semel Institute for Neuroscience and Behavior (photo by Gene Veritas)

Measuring brain energy

A psychiatrist specializing in depression and Alzheimer’s disease, Dr. Leuchter (pronounced LUKE-ter) frequently employs quantitative electroencephalography (quantitative EEG) to measure the energy emitting from people’s brains. One example: a group of 27 HD subjects he and others observed for a study published in 2010 and funded by CHDI Foundation, Inc., the nonprofit virtual biotech dedicated exclusively to the discovery of HD treatments.

Allan Tobin, Ph.D., at the time the head of UCLA’s Brain Research Institute and a senior scientific advisor at CHDI, had asked colleague Leuchter for assistance in finding HD biomarkers, signals that reveal the progression of the disease and/or the effectiveness of a medication.

As the number of HD clinical trials expands exponentially, the search for useful biomarkers has become one of the hottest areas in Huntington's disease research. (Click here to read about one new potential biomarker.)

As Dr. Leuchter pointed out, neurological and psychiatric disorders are “much more limited in diagnostic tests for the organ that we are studying than any other branch of medicine.” Cardiologists insert catheters into the heart, and gastroenterologists use scopes to view the stomach and intestines.

“If you’re a psychiatrist, we talk to people, which is great, but we don’t have physiologic tests that guide decision-making,” he added.

Scientists and doctors rarely put electrodes in living human brains or take biopsies of brain tissue. However, they have been measuring brain energy with EEGs for more than a century, Dr. Leuchter explained.

As he demonstrated in his lab (see photo below), today patients undergoing testing wear a cap with 35 separate EEG electrodes, or contacts, that touch the head. The attending researcher stretches the cap over the patient’s head. In contrast with the traditional EEG, which involves one-by-one placement of the electrodes on the head, this method is quick, efficient, and less burdensome to patients, he noted.

Above, Dr. Andrew Leuchter points out the electrodes on the EEG cap worn by research subjects. Below, he explains digitized EEG readings displayed on a computer monitor. (photos by Gene Veritas) 

“We find that this helps to standardize our measurements of brain activity, and that we can place the electrodes in about 15 minutes,” Dr. Leuchter said.

EEG is inexpensive, convenient, and easy to administer. Additionally, it does not expose patients to radiation or require them to lie inside a machine such as an MRI scanner, he noted.

“You can tote it wherever you like,” he said of the EEG device.

The brain’s pacemaker

As they had hoped, Dr. Leuchter and three other UCLA researchers discovered abnormal EEG readings in HD patients with just mild symptoms.

“But the really intriguing thing there was that, even in people who were gene-positive but premanifest, we could see differences in brain function estimated 15, 20 years out from diagnosis,” Dr. Leuchter said, referring to signals of future decline. “So we thought this could be something that could be useful for treatment development.”

As Dr. Leuchter explained, “the brain like the heart has pacemakers.” Healthy brains produce lots of high-frequency waves. Brain illnesses commonly result from changes in the firing of the pacemaker, resulting in a greater quantity of low-frequency waves.

“What we found is that years before people start to show symptoms with Huntington’s, they’re producing more low-wave energy,” Dr. Leuchter said. So it’s a very subtle indicator that the pacemaker of the brain is starting to slow down.”

Scientists cannot predict the actual onset and progression of symptoms from EEG signals. However, as noted below, they did discover a correlation between the severity of genetic mutation and EEG readings.

Clear genetic impact on the brain

Furthermore, the team observed that, in contrast with healthy brains, the distribution of different types of waves across the different regions of the HD brains became more uniform. “The regions of the brain start to look more similar than different,” he explained.

Researchers have not yet discovered what this phenomenon means.

“We know that the brain has enormous functional reserve and that people call on every cognitive and emotional resource they’ve got to try to keep everything functioning at optimal efficiency,” Dr. Leuchter continued. I don’t think we know what’s compensatory and what’s an early sign of illness.”

Reflecting on another facet of the research, Dr. Leuchter explained that, in general, brain function tests do not correlate with genetic factors.

However, he and his team did find a correlation between the degree of HD genetic mutation and the severity of the changes in the EEG readings.

“Nobody had seen that,” he recalled. “We got excited about that, and that’s what we’ve been trying to follow up on.” These findings will contribute to the search for biomarkers and treatments, as explained below.

Examining brain tissue

A neurophysiologist and veteran basal ganglia researcher, since the late 1960s Dr. Levine has studied these deep, inner parts of the brain that control such actions as voluntary movements. He began to study HD in the 1990s as genetic mouse models with HD-like symptoms became available. His lab has published more than two dozen papers about these mice.

The nuclei of the basal ganglia are significantly compromised in HD, especially in the striatumSpecifically, Dr. Levine has examined how neurons communicate with each other in the cortex and striatum at cellular and molecular levels using tissue from the HD mouse models.

One of the latest techniques for studying the cells in the HD mouse models is optogenetics, in which specific types of brain cells are stimulated with light.

“I can look very closely at mechanisms,” Dr. Levine explained. “I know which types of neurons I am looking at and how they change at a very mechanistic level.”

Michael Levine, Ph.D., veteran HD researcher (photo by Gene Veritas)

Two key goals

Melding approaches, and with the expectation of CHDI support, Drs. Leuchter and Levine now seek to answer two important questions.

The first involves comparing EEG data from both mice and humans to refine the search for biomarkers. Researchers have already made the key discovery of EEG signals common to mice and humans.

“It’s actually pretty uncommon in science that you can see a very similar signal across species, that you can see something very similar in the brains of humans and the brains of animals,” Dr. Leuchter said.

If the Leuchter-Levine project confirms the degree of that similarity, that could mean  potential drugs tested in mice could ultimately be used for human clinical trials, Dr. Leuchter observed.

The second question focuses on the testing in HD mice of a CHDI-developed compound aimed at lowering the amount of mutant huntingtin protein, the major culprit in the disease.

“If we do see a link between lowering of mutant huntingtin and change in the EEG biomarker, this could be used to develop a number of therapeutic agents,” Dr. Leuchter said. “A whole line of research could develop out of this.”

From molecule to the whole brain

Drs. Leuchter and Levine estimated the project will take two years to complete.

As Dr. Levine put it, researchers hope the CHDI-developed compound will restore the EEG signals in HD patients to normal.

Dr. Leuchter reflected on the significance of the project and his collaboration with Dr. Levine: “The fact that in something like Huntington’s disease you’ve got a protein that is affecting how the nerve cells are functioning and altering the way they produce and utilize energy – it’s really a gateway to understanding the connection between what is going on at the deepest molecular level of the cell and what we’re able to see with the brain waves the individual is putting out. We can actually potentially link everything going from the level of the gene all the way to whole-brain function.”

In another potential future project, Dr. Leuchter would like to obtain EEG readings from asymptomatic gene carriers over two to three years to better measure the changes in signals over time.

Drs. Leuchter and Levine (photo by Gene Veritas)

Participation and a positive attitude

Both researchers expressed gratitude to the HD community and fellow HD researchers for their dedication to the cause.

“There are not that many people with this illness, so people get asked a lot to participate in different studies where they’re poked or prodded or scanned,” Dr. Leuchter said. “We are very grateful to those who are so generous with their time, because without their help we could not conduct these research studies.”

Dr. Levine added that he is impressed with the “very positive and sharing attitude of the investigators who do research in HD and who are looking to help the patients.”

While interviewing these two researchers, as an individual racing against the genetic clock of HD, I was once again moved to witness the creativity and enthusiasm of scientists engaged in the quest to save affected families from the devastation of Huntington’s.

(Later this month: from the East Coast a report on Yale School of Medicine researcher Doug Rothman, Ph.D., and the mystery of the mitochondria in Huntington’s disease. Please remember during HD Awareness Month to donate generously to the Huntington’s Disease Society of America or the HD cause of your choice!)