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Interview with Dr. Zaven Khachaturian
President & CEO of The Lou Ruvo Brain Institute
& Keep Memory Alive

March 30, 2007

 

 

Introduction:

Zaven Khachaturian, Ph.D. is the President and CEO of Keep Memory Alive, Lou Ruvo Brain Institute, a Las Vegas-based non-profit organization dedicated to finding a cure to Alzheimer’s and other neurological diseases.

Alzheimer' s Disease and dementia affect millions of Americans, creating huge problems for those with the illness and for their caregivers.  Equally important is the economic burden on our health care system.  By some estimates, the annual cost exceeds $100 billion dollars.  After heart disease and cancer, this is our country's most costly illness.

The mission of the Lou Ruvo Brain Institute is "dedicated to the conquest of: Alzheimer's, Huntington's, Parkinson's, Amyotrophic Lateral Sclerosis ( ALS), and other chronic brain disorders. The Institute fosters the creation of worldwide cooperative research networks to: a) develop new detection technologies for early and accurate diagnosis of dementia and b) facilitate the development of treatments for various forms of memory impairments.  The LRBI aims to build a unique national research resource in Nevada to accelerate the process of testing and validating new interventions that will slow or prevent the progression of neurodegeneration, which is a primary cause of most memory disorders."  (Taken from the Keep Memory Alive website)

Since the Institute is located in Las Vegas , this city was chosen to be the most appropriate location for this interview.  To find an inspirational setting, we chose to meet on a small patio adjacent to the magnificent fountains of Bellagio.  As the water danced high into the early evening sky, one could not help but feel the far reach and lofty goals of the Institute's mission.

 

 

Spencer:


Nearly five million people nationwide have some form of a serious memory disorder.  Alzheimer’s disease and related memory problems present a major public health issue, and place a large burden on both caregivers, and our economy.  The Lou Ruvo Brain Institute is working to find cures for these and other neurological diseases.

For someone who is not already familiar with the Institute, can you please explain how the Institute is working to achieve the ultimate goal of finding solutions to some of the dreaded disorders?


Dr: Khachaturian


That’s a very good question.  The Lou Ruvo Brain Institute is going to take a different approach than other similar organizations, where the primary focus is on a single disease category, such as Alzheimer’s or Parkinson’s or Huntington's.  In contrast the Lou Ruvo Brain Institute will emphasize the clinical symptoms that are relevant to the patients; problems such as memory disorder, movement disorder, and mood change. Dementia is the larger category of clinical features that is shared by a number of neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s.   

So the focus of the Institute is to look for the common underlying biological mechanisms that cause problems in memory, in all the neurological disorders, regardless of the diagnostic label. The goal is to build bridges across disciplines.  Most previous approaches to understand neurodegenerative disorders have tended to build silos.  Their efforts have focused only on a single disease, for example, Parkinson’s, or a particular theoretical underpinning.  In contrast, the Institute will be looking at across the board, trying to connect the biological underpinnings of the disease with the genetics, with the clinical; using an inter-disciplinary or what’s called systems approach. The Institute will be primarily an outpatient operation.  People who have problems will come to the clinic for a comprehensive evaluation . The clinic will have neurologists, psychiatrists, neuropsychologists, nurses, imaging people, biologists, as a team to look at the patients, evaluate them in a comprehensive way to determine the nature of the primary problem, then divert to a more specialized evaluation for a particular problems of memory or movement disorder.

In terms of the research operation, the Institute will be operating more like a virtual entity, building a network of collaborators across the world.  We already have established connections with Paul Greengard at Rockefeller University. Dr. Ann Young, who is the Chairman of Neurology at Harvard, is on our advisory board.  She’ll be helping us.  Dr. Ronald  Peterson, who is at Mayo Clinic, will also be on our advisory board, and he’s setting up the clinical operation.  Dr. Trojanowski, from University of Pennsylvania, will be setting up the neuropathology and biomarkers operation.  There will be a wide network of collaborators doing the research with the  primary goal of  identifying people who are at risk for the disease.  The reason for this is that many neurodegenerative diseases such as Alzheimer’s start many years before any clinical signs appear or the disease is diagnosed. During this prodromal period, of the disease are no symptoms, but the disease process is slowly advancing.

There are many disease with similar patterns of disease progression.  For example, in the case of cancer there are  biomarkers e.g., a protein that indicates whether a person has the disease.  Sometimes an imaging technique is used for this purpose of early detection. In the case of dementia, there are no well-validated early markers that could be telling whether a 20 or 30 year old person already has the disease.

Our ability to detect the disease with some certainty is an important prelude for developing drugs to prevent the disease. If we want to prevent a disease, we have to catch it very early because by the time the clinical picture appears, it’s too late.  After the symptoms appear, current treatments cannot reverse the disease and they work for a short time.   

The research program of the Institute will be focusing on recruiting  as volunteers people who are at risk for the disease, but without any symptoms and  still well-functioning.  The goal of the Nevada Vital Initiative is to recruit some 18,000 baby boomers who will be evaluated every year.  This will entail taking  some blood samples, DNA and imaging data.  Every year we hope this information will lead to the early indicators or biomarkers  that predict who is going to get the disease.

A subset of these volunteers will be asked to participate in a program whereby we will redesign their homes to allow the placement electronic detectors that permit remote assessment of health status or activities of daily living. We feel that telemedicine and various electronic non-invasive technologies is the future for providing health care to older individuals people living in remote areas with limited access to doctors or hospitals. In the future medicine or medical care will be delivered in the home, rather than a person traveling to a clinic. We can do a lot of things in the home.  Right now, there are robots that could help people.  You can do surgery across the Atlantic.  Why couldn’t you do a health assessment with the various low cost devices in the home? Before the discovery of the telephone people could only communicate in a face to face meeting.  The telephone changed the pattern of communication between people.


Spencer:


Michael J. Fox is currently living with Parkinson’s.  The Michael J. Fox Foundation is his creation, dedicated to finding a cure for this disease.  One primary objective of the Fox Foundation is the promotion and funding of stem cell research.  Many believe that the cure for Parkinson’s Disease might lead to the cure of other degenerative, neurological disorders, such as Alzheimer’s.  Is the Lou Ruvo Institute working with stem cell research?  And if yes, is the government funding this form of research, or is it being funded privately?


Dr: Khachaturian


One thing you need to be very cautious, as a science reporter or writer, is that reporters for the popular media tend to look for easy answers and ready to accept at face value the reports of scientific findings or the merits of a particular discover of a new treatment approach.  Sometimes these reports are exaggerated in order to create publicity for one’s own work or to influence the stockholders or potential investors of a company.  So a science reporter needs to question and be very careful in evaluating newspapers stories.  Sometimes you hear results of a study, saying that they found that if you eat more of this or that, it’s beneficial.  Those need to be very carefully evaluated because sometimes they turn out not to be correct.  The only way we can find out whether a procedure is useful is by clinical trials.

Clinical trials are designed to determine efficacy of a drug, or a procedure. Clinical studies designed to evaluate the efficacy of treatments are conducted in a very carefully controlled way where only a portion of the subjects receive the treatment while other are given a placebo.  In the case of the stem cell, the concept is very useful, and has a lot of appeal because the notion is that these cells that are undifferentiated; they haven’t made up their mind yet whether they want to be a muscle, or they want to be a bone, or they want to be a neuron.  And if they’re going to be a neuron, what kind of connection they’re going to make.  So the idea of taking these undifferentiated cells, putting them in the brain or some organ, and guiding it, is appealing.

Having said that, the merits of the stem cell research has been overplayed for political purposes and important scientific questions have been obscured or ignored..  The use of stem cells for treating Alzheimer’s is not likely to be beneficial unless these patients are identified very early in the disease process.  The situation is very similar to computer with memory problems in the hard drive; replacing the hard drive will allow the computer to function but all their old stored memories will be lost.

So for diseases like Alzheimer’s that deal with memory, it’s not likely to be a very useful technique.  But that cannot be said for problems like spinal cord injury, where the relationship is very specific connections between two points.  Parkinson’s is a disease where there are specific pathways that are affected, and they affect how the muscles are in control.  So stem cell applications cannot be applied equally for all the diseases.  You need to be very careful.

The other important thing is that in the case of Parkinson’s, many years ago, the treatment that everybody thought of was transplant.  They thought that if you take tissue from fetal brains, put it into brains of a rat, these cells would reconnect and be helpful.  And that was thought of as the solution.  Well, it turned out not to be so.  There is the possibility that may not turnout to be as simple or straight forward solution to neurodegeneration. What we need to do is learn how stem cells receive their message.  What are the biological signals that control and guide their expression or activities? The critical challenge is to discover how stem cells become neural cells and how these nerve cells make the correct connections with other cells; if a stem cell doesn’t make the right connection, it’s useless.

Yes, stem cell research is very important, but the important thing is what questions one asks.  Currently are there available e tools to answer those questions?  The answer is yes.


Spencer:


The Keep Memory Alive [KMA] is the foundation for the Lou Ruvo Institute.  What does The Keep Memory Alive do to benefit the Lou Ruvo Brain Institute?  And, does The Keep Memory Alive work in partnership with other organization?


Dr: Khachaturian


The primary mission of Keep Memory Alive is to raise funds to support the Lou RuvoBrain Institute.  Lou Ruvo Brain Institute is the programmatic arm of KMA.  Concerning the question   whether LouRuvo Brain Institute is working  with organizations.  Very definitely.  We're forming partnerships with the Huntington Disease Foundation.  With Parkinson's, we'll be working with the Michael J. Fox group and the Alzheimer's Association. 

This morning, I ran into a group that's interested in a syndrome called William’s Disease.  There's another group that's involved in autism.  So we're looking for a partnership where the primary emphasis or interest is to understand how nerve cells become dysfunctional, why they die.  Any organization that is interested in that, we're forming partnerships.


Spencer:


And how about the Hereditary Disease Foundation?  Are you involved with them at all?

Dr: Khachaturian


Yes, very much.  In fact, we're exploring how the two organizations can work together.


Spencer:


What is the Common Threads Think Tank?


Dr: Khachaturian


The Common Threads Think Tank was actually a conference that was done jointly by the Hereditary Disease Foundation and the Ruvo, precisely along the lines of what we were talking about.  We wanted to see whether there are underlying features that are common to Huntington Disease and Alzheimer's.  And the conclusion is that in both cases, there are abnormal protein foldings.  In both cases, there are mitochondrial defects.  These are organelles in the cell that make energy available to a neuron.  And neurons are very dependent on energy.  They consume more calories.  They use more sugar than any other organ in the body.  And if you deprive a nerve cell of calories, they're in bad shape.  The worst-case scenario is stroke.  That's what happens if certain parts of the brain are not properly perfused and the cells aren’t getting the right amount of glucose and oxygen. The cell starts dying.

Well, in other degenerative disorders, a somewhat similar pattern happens.  It happens at a slower pace, over a much longer period.  Instead of ten or 15 minutes, years.  So that's why those are important issues to understand how energy is made available to a neuron in order to be healthy; how neurons make new proteins without messing them up.


Spencer:


I read that if the onset of memory loss could be delayed by five years with independent functioning maintained, the number of people affected would be reduced by half.  The Nevada Vital Aging Project has been working to discover interventions that can be used long before memory problems appear.  Can you explain the recent advances in imaging and biomarker technology that would allow one to detect neurodegenerative processes before the onset of symptoms?


Dr: Khachaturian


Imaging is used in several ways.  There are some techniques that would allow you to measure metabolic changes.  For example, there's a technique called positron emission tomography, that measures the amount of glucose that's being used, or something similar to glucose, and you can measure that by changes in the color.  Areas that are very active, they're using healthy cells, using a lot of glucose; they will appear red.  Areas that are not working well, they appear blue.  So using such imaging techniques, scientists can tell parts of the brain that are working.  And using these techniques, scientists have been studying people who are at risk for the disease.  If the parents have the disease, yet they don't have the disease, but they follow longitudinally.  And they have found that up to two years before clinical symptoms appear, they see patterns that are indicative of Alzheimer's.  So that's one technique.

There is also another technique, which is magnetic resonance imaging that can measure the structure of changes. Through that, they look for changes in the structure.  They've found that the brain actually starts shrinking.  It gets smaller.  Parts are being lost.  And you can do that up to a year before. 

There's another technique.  By giving a person a compound that's given into the blood, this compound circulates through the circulation, gets to the brain and would go and bind to some of the abnormal proteins that are the lesions of the disease.  These are called amyloid proteins.  These compounds go in and attach themselves to these amyloid proteins.  The compound is designed so that when you image it, you can see it.  With this technique you can see in the live patient the formation of the lesions, and that technique is being now tested in a large clinical trial.  So there is a major effort on the way.  The effort is called Alzheimer's Disease Neuroimaging Initiative.  Is includes some AD institutions, several pharmaceutical companies, several imaging manufacturers like GE, Siemens, Phillips, who are partners in following patients and measuring their brain changes. Dr. John Trojanoski is helping set up our biomarker's program.  He's collecting blood samples, and looking for abnormal proteins in the cerebrospinal fluid, and looking for how you can detect the disease by the presence of these proteins.  So those are some of the approaches that are being taken, and the goal, as I indicated, is to be able to identify people with the disease as early as possible.


Spencer:


Are there any promising treatments, or prevention strategies, and what can aging people do to reduce their risk of dementia?


Dr: Khachaturian


Well, right now, there are no treatments that can relive the symptom.  The treatments they have are effective for about six months, maybe a year.  If you're lucky, two years.  These treatments, what they do is they change the amount of neurotransmitter that's available.  The part of the disease process involves the diminution of the neurotransmitter.  The neurotransmitter is a chemical that is released by nerve cells, and nerve cells communicate by such chemicals.  Genetically, these are called neurotransmitters.  One specific one is called acetylcholine , which not enough is made in Alzheimer's, and it's really the cause of why memory disorders occur.  If one cell wants to talk with another, a small amount of it is released.  It's diffused, and the cell would receive it, and will respond.  Well if not enough are being made, one strategy people used were to see if they can make this cell make more of it.  They found slowing the action of an enzyme that breaks down acetylcholine would work.  Now there are four drugs as treatment that work on this principle; these are called Acetylcholinesterase Inhibitors.  The problem with these drugs is that after awhile as the disease progresses, the cell is dead. Treatment can't do anything because the cell that's going to receive the benefit is gone.  It's like putting more has in the tank of a car that has a big hole in it.

So the future is to look for what you can do to preserve the cell; how to prevent it from dying.  One idea is to use a drug that's been developed for diabetes, because they've found that Alzheimer's involves diabetes- like changes.  So by trying this drug, they've seen some beneficial affects.  That drug is under trial now.  Another approach is to reduce cholesterol.  There are some drugs that have been used for cardiovascular that are being used.  So there are a number of ideas that are very promising.  Now, there is the speculation that certain dietary habits like anti-oxidants might be beneficial.  Exercise and keeping the mind active might be beneficial.  These do not change the course of the disease.  They just slow it down.


Spencer:


What forms of treatment are currently available for treating patients who already have memory loss, and what new research is the Institute currently working on?


Dr: Khachaturian


Well, there aren't really that many effective treatments for memory loss.  The only ones are the acetylcholinesterase inhibitors.  There is another strategy for dealing with the disease, this drug called memantine.  It regulates the calcium inside the cell.  Nerve cells inside the cell, the calcium concentration, is substantially less than outside.  That's a common phenomenon with all excitable cells.  The same thing is true in heart muscles, generally.  And when a cell gets excited, receives a message, for a very brief period, calcium comes in and turns on certain messages.  And then it's pumped out very quickly.  If the calcium stays inside, it causes damage.  In fact, that's what happens in strokes.  In strokes, there are some neurotransmitters that allow the calcium into the cell.  And it's the high calcium level inside the nerve cell that kills it.  The same thing happens with heart muscle.  When heart muscle doesn't get enough glucose, the calcium levels go up, and that's what kills it.  That's why you use calcium channel blockers. 

So that concept is being used as a treatment.  It's one of the two strategies that's used, as I indicated.  It's of limited utility because the key problem in neurodegeneration is the loss of the cells.  So what we need to do is find out how you can prevent the cells from dying.  And one of the important ones is to see how you can make the energy supply available.  That's why treatments like the ones being used in diabetes are useful.  Ultimately what's going to be useful is finding out the message by which nerve cells repair themselves.  There are neurotrophic factors that stimulate nerve cells to make new branches.  So those are being tried. 

So there is a large number of ideas, but they all need to be tested in clinical trials.  One of the big problems we have in the field is that we don't have adequate animal models.  Whereas in other diseases like cancer and so on, you can create a rat or a mouse with the cancer.


Spencer:


You can't create memory loss.


Dr: Khachaturian


You can't create memory loss.  And so that's where the difficulty is.  But compared to 20-50 years, ago, we have a lot of promising leads.  I think the next ten years or so, we'll see some effective treatments coming.  So stay tuned.  Keep asking questions.


Spencer:


Please tell me about the Creativity and Vital Aging Program.


Dr: Khachaturian


Well, the notion there is that although we may not be able to correct the memory problems, but there are non-invasive things we could do with older individuals, such as creating an environment where they are able to learn dancing, or take painting classes, or pottery, or do exercise.  And those activities have been shown to be beneficial to people.  So we're going to create a program at the Institute in partnership with the Performing Arts Center, with the drama school, with the arts school, to bring artists to come to the Institute and bring the citizens to come to take classes in poetry, or anything that would stimulate their brain.


Spencer:


So how is it beneficial?  It stimulates their brain in what way?


Dr: Khachaturian


Well, there is some evidence that people who have higher education, or people who have challenging occupations tend to get the disease much later.  Animal studies show that if you stimulate the brain, or put an animal in a stimulating environment, the number of dendrites, these are the connections to a nerve, increase.  And very likely, the same thing happens in humans.  So staying active stimulates the growth of these neurons to make new connections.  That's the logic behind it.


Spencer:


So we should keep reading books until we're very old?


Dr: Khachaturian


Reading books, or always challenging; challenging the brain, doing something difficult.  Routine doesn't do it.  Learning a new language; do something that you haven't done.  If you're a klutz,  do carpentry, or do something where you're trying to solve a problem.


Spencer:


Could you please explain the Institute's experimental kitchen?


Dr: Khachaturian


Well, the Institute is going to have a Museum of the Mind where there will be exhibits and displays on the various aspects of the brain-mind-body problem.  It will also have a kitchen by Wolfgang Puck, and the idea there is to make that kitchen experimental, so that we can design new menus, new ways of serving food.  One of the changes that occur in older individuals is, besides the decline in vision and hearing, other senses decline, particularly the sense of smell.  Many older individuals are anosmic.  They can't smell well, and their taste buds don't taste as much.  They tend to put on too much salt because they're trying to enhance the senses.  So we need to do research on how you could make food more tasty, smell better, because those are important elements by which people enjoy quality of life.  So the kitchen will try to use the latest knowledge about the sense of smell and taste, and vision, to make food more appealing visually, taste better, smell better, and at the same time make it healthy.  So, the idea would be to create new menus, new ways of serving.


Spencer:


No trans fats?


Dr: Khachaturian


No trans fats, right.


Spencer:


What did you do before coming to the Institute and what inspired you to make this career change?    


Dr: Khachaturian


Well, I didn't really do that much of a career change.  I'm trained in neurophysiology.  Neurophysiologists are people who study the physiology of the nervous system, and my interests were in learning and memory.  I was at NIH  many years, building programs.  So I'm building programs here.  So it's not much of a change.


Spencer:


The Institute will be moving into a new facility next year.  Will this be an ordinary medical building, or as some have said, a cultural landmark?


Dr: Khachaturian


I don't know whether it will be cultural, but it will be an architectural landmark, because Frank Gehry is designing the building.  And anything that Frank Gehry designs is an icon.  And to put a building like that in the middle of the desert, it's certainly going to attract attention.  He did it in Spain with the Guggenheim Museum in the middle of nowhere, and it's become a major attraction.  And the idea of using Frank Gehry to design an institute that's devoted to the brain science will make the study of neurodegenerative diseases highly visible.  I think that's inevitable.  That's what we're hoping for anyway.