ONE-ON-ONE
- August 2002
by Ed G. Lane
'No One Has Ever Recovered from
Alzheimer's Disease'
The director of UK's Sanders-Brown Center on Aging discusses medical
technology's role in preventing dementing illnesses
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William R. Markesbery
William R. Markesbery is professor of pathology and neurology
and director of the Sanders-Brown Center on Aging at the University
of Kentucky. He received his M.D. from UK in 1964 and completed
training in neurology and neuropathology at Columbia-Presbyterian
Medical Center in New York. Dr. Markesbery’s research focuses
on Alzheimer’s disease and the aging brain. He has served
as president of the American Association of Neuropathologies
and as chairman of the Medical and Scientific Advisory Board
of the National Alzheimer’s Association. He has also served
on a National Institute of Health study section and the National
Advisory Council of the National Institute on Aging. He is the
principal investigator of the Alzheimer’s Disease Research
Center and a program program project grant on Alzheimer’s
disease.
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Ed Lane: As the life spans of men and women continue to increase, what
impact will living longer have on age-related afflictions such as Alzheimer’s
disease (AD)?
William R. Markesbery, M.D.:
Age-related diseases will continue to increase unless we find a way
of preventing them.
EL: How many Americans are
projected to develop Alzheimer’s disease?
WM: Currently, there are approximately
four million Americans over the age 65 with the disease. By the year
2050, it is projected there will be 14 million persons with this disorder
in the United States.
EL: In addition to AD, what
other age-related diseases are becoming more prevalent?
WM: As human longevity increases,
Parkinson’s disease, some cancers, heart disease and strokes
increase with age.
EL: How long has the Sanders-Brown
Center on Aging at the University of Kentucky (COA) been in existence?
WM: The Center opened in the
fall of 1979.
EL: Have you been the director
since COA’s inception?
WM: I’m the only director,
so far.
EL: Many of the COA’s
staff are from other states and countries. Why have they come to the
University of Kentucky to conduct their research?
WM: The Center has developed
a reputation in the area of neurodegenerative diseases and very specifically
in Alzheimer’s disease. Investigators have come here to work
because we have a good track record in AD. We try to recruit the best
scientists and clinicians that we can from all over the country.
EL: How many individuals comprise
the Center’s staff and what are some of the COA’s primary
areas of study?
WM: The Center has 26 faculty
members and about 200 overall employees. The major areas in which
we have interest are Alzheimer’s disease, stroke, and changes
in the immune response with aging.
EL: What does the Biostatistics
and Data Management Core do at COA?
WM: This part of our team
supports research activities by helping with the planning of research
studies, developing the power analysis (the number of subjects needed
to make a study statistically reliable), and preparing the statistical
analyses of studies. They also maintain databases for various studies,
especially as they relate to Alzheimer’s disease.
EL: So COA has been maintaining
research data for over 20 years?
WM: Correct. The Center didn’t
have a Biostatistics and Data Management Core in the beginning, but
we’ve been maintaining data since 1981 or 1982.
EL: What services does the
Clinical Core provide at COA?
WM: The Clinical Core has
a large memory disorders clinic at UK which serves patients from the
tri-state area; actually, we get referrals from way beyond that. It
also operates an outreach clinic in Prestonsburg, KY, which serves
patients who would not normally have access to the quality evaluations
and care that we offer, and a memory disorders clinic in conjunction
with Meharry Medical College (http://www.mmc.edu/) in Nashville.
EL: What is the key function
of the Education and Information Transfer Core at COA?
WM: The major role of that
core is to hold conferences and educate healthcare providers about
AD and related diseases. It also has the task of disseminating information
about neurodegenerative diseases to research and clinical scientists,
caregivers and lay public.
EL: COA recently expanded
its educational efforts in the field of gerontology. What does that
program offer?
WM: COA has a PhD program
in gerontology, which is one of only five in this country. It has
a unique emphasis on aging and health. It has just graduated its first
class. We also have a master’s certificate program in gerontology.
In addition, we train many postdoctoral students.
EL: The Neuropathology Core
at the COA maintains a tissue bank of brain specimens for AD investigations.
How important are brain specimens for research?
WM: Brain specimens are extremely
important, because there is no perfect animal model of the disease;
thus, to study the disease you really have to study it in humans.
There are some mouse models of AD, but they are not ideal. So, the
brain bank and the utilization of tissue are very, very important.
COA also has a control group of between 400 and 500 individuals who
volunteer to have neuropsychological testing each year and to have
physical and neurological examinations every other year. They’ve
also agreed to brain donation.
From this study, we are learning
a lot about normal aging in the brain. This is an extremely important
topic because there is some overlap between normal brain aging and
Alzheimer’s disease. One of the strengths of this center is in
neuropathology because we have normal control individuals that teach
us not only about brain aging, but also serve as comparative controls
for individuals with Alzheimer’s disease. I can’t overemphasize
how important that really is.
The Center also has a rapid
autopsy program. There are all kinds of changes that take place in
the brain in the interval between the time of death and the autopsy.
At COA we do them as quickly as possible (within two to four hours),
and we do them more rapidly than anybody else in the country. This
gives us very unique research tissue to use for biochemical and a
variety of other studies.
EL: Do you provide these brain
specimens to other centers around the country to help them in their
research, or do you use them exclusively here?
WM: The 28 AD centers cooperate
very closely. We meet twice a year and there is a sharing of resources
and information. Our center does share with other centers and other
investigators around the country, but only after our executive committee
carefully evaluates each proposal and gives its approval. I want to
make sure that’s clear.
It’s important for the
Alzheimer’s disease centers to share with each other. Some centers
are strong in genetics, others are strong in epidemiology, neurochemistry,
neuropathology, and a variety of other research areas. Because AD
centers don’t all work in the same areas, there’s a lot
of cross talk and data sharing.
EL: The Nun Study at COA has
received a great deal of national publicity. What is the purpose of
this study?
WM: It’s more of an epidemiologic
study, but it also has, at its end point, autopsy of the brain and
clinical – pathological correlations. This research allows us
to study the individual during life, by doing neuropsychologic testing
and examinations, and then correlating that data with what we find
at autopsy. The nuns have been extremely helpful by allowing us to
have their medical records and written data from the time they entered
the convent.
The nuns have similar medical
and dental care, most of them have eaten out of the same kitchen,
and they do a similar type of work – they are teachers. They
have not borne children, do not smoke, and don’t drink. These
environmental factors cannot be controlled in a normal population,
that’s one of the factors that makes the Nun Study unique.
EL: Where are the nuns located?
WM: They are located in a
number of different convents around the United States.
EL: I realize that these studies
may not have arrived at any final conclusions, but have there been any
preliminary findings reached from the Nun Study and other studies COA
is now conducting?
WM: I believe that the key
factor in AD is prevention and to understand how to prevent it, we
have to know the pathogenesis and cause of the disease. Our center
has made many important discoveries in defining the mechanisms of
neuron death as it relates to AD. There are too many to describe,
but in our last five year review by National Institute on Aging (NIA),
our Alzheimer’s disease Research Center had over 500 publications
in peer-reviewed journals.
One thing that really stands
out in both the Central Kentucky and the Nun Study is that many individuals
have normal mental status test scores but at autopsy have many of
the changes of AD in their brain – senile plaques and neurofibrillary
tangles. That would mean that these individuals have brain reserve
that allows them to maintain normal cognition in the face of changes
in their brain. So, one of the questions is, what is brain reserve?
Why will one 85-year old individual function completely normally and
have a lot of senile plaques and neurofibrillary tangles and another
85-year old individual become demented with similar numbers of plaques
and tangles? Brain reserve is very important.
EL: Do genetic factors affect
the incidence of AD?
WM: The genetic aspect of
AD is probably the area that has been most exciting in the past 10
years.
There are now three genes
that we know cause AD. If you carry any one of these three genes,
this will absolutely predict that you’re going to get the disease.
This is usually early onset AD, between ages 55 to 65. But these three
genes, called presenilin one, presenilin two and the amyloid precursor
protein gene, represent only about two percent or less of Alzheimer’s
disease.
There is probably a gene on
chromosome 10 that causes many cases of late onset AD (over 65 years
of age). Another important genetic factor in AD is apolipoprotein
E (APOE). So, the importance of knowing whether you are at a genetic
risk is really very critical because some neuro-protective therapies
are available right now.
EL: What are other representative
studies now being conducted at COA?
WM: COA has a one million
dollar a year program project grant in AD. This is a grant that is
going into years 15 through 20, which means that the COA has been
relatively consistent in its ability to maintain this large grant.
It has four projects and two cores working in a cohesive fashion to
study oxidative stress in AD. One of the hypotheses about why nerve
cells degenerate in AD is that they undergo oxidative alterations
and die. And this study is defining the mechanisms of how oxidation
causes neuron death. There is an increase in the oxidation of lipids,
proteins, and DNA and AD. So, defining the basic pathogenetic mechanism
of how neurons die can lead us to ways of preventing it. The oxidative
stress program project grant is really an important one.
COA also has a very important
study underway that uses the basic science information about oxidative
stress in the prevention of AD. This is a study called Prevention
of Alzheimer’s disease with Vitamin E and Selenium (PREADVISE).
In this study, the Center is evaluating 12,000 men over the age of
60 to see if vitamin E and selenium can prevent or slow the onset
of AD. This is part of a study of 32,000 men called the SELECT Study
which studies vitamin E and selenium to prevent prostate cancer. The
National Cancer Institute is funding that study to prevent prostate
cancer; the National Institute on Aging is funding our studies. This
research takes basic science information learned in the laboratory
and applies it to attempt to prevent the disease.
EL: What are some of the preventive
measures for AD currently being studied?
WM: One regimen is large doses
of vitamin E, large doses of vitamin C (which makes vitamin E more
effective as a free radical scavenger), and large doses of folic acid.
Low folic acid levels have been clearly shown to be associated with
brain atrophy. High levels of homocysteine are a risk factor for AD
and folic acid will lower homocysteine. However, it is important to
understand that I don’t want to be viewed as pushing any specific
medications.
Other studies have shown that
nonsteroidal anti-inflammatory drugs seem to have an effect on slowing
the onset of the disease or preventing it. If you take a nonsteroidal
anti-inflammatory drug you should do that under a doctor’s care
because of potential problems of developing GI bleeding.
There are some epidemiologic
studies that suggest the use of lipid lowering agents, the “statins.”
There are trials underway using the statins. We don’t recommend
statins routinely but if you’re taking them, they may be a neuroprotectant.
There are studies that show
that women who have taken estrogen for a long time also may be at
lower risk for AD. Recent studies suggest that women should discontinue
estrogen because of the potential of developing ovarian and other
cancers. If your risk for AD is very high, then you have to weigh
that against your risk for ovarian or breast cancer.
Diet is extremely important.
Calorie restriction seems to protect against many of the factors of
aging and probably is important in AD. There are also several studies
that show that if you eat lots of seafood, the risk of AD is lower.
EL: You mentioned vitamins
E and C. Do those vitamins need to be in natural forms or can you just
take vitamin E capsules?
WM: We give everybody with
AD or at risk for AD vitamin E capsules. But, there is a study that
just came out suggesting that what you get in your diet is probably
more important than taking it in supplement form. But, again the numbers
in the trial study were not that large and there will need to be at
least several other studies to clarify this issue.
Another thing that also is
part of prevention management is aerobic exercise. It has been shown
in rodents that aerobic exercise decreases aging in the brain and
increases neurotrophic factors which enhance repair of damaged nerve
cells.
EL: What are some of the early
symptoms of AD?
WM: The earliest symptom is
a decline in short-term memory. That is characterized by not remembering
names of familiar individuals, losing things frequently in your home
environment, by repeating questions and comments, forgetting appointments,
forgetting to take your medications, or very simple things like not
remembering what you were told an hour before.
Visuospatial impairment can
develop early and may be characterized by confusion with directions,
getting lost in familiar surroundings, or having difficulty dressing.
Other symptoms can be in language dysfunction such as difficulty in
finding the right word to use or misusing words.
You also can have behavioral
and emotional changes as early symptoms. But the most common early
symptom is decline in short-term memory.
EL: Are there other illnesses
with symptoms that may mimic AD?
WM: There are many. That’s
why everyone with any kind of dementing illness needs a very thorough
work-up, because some of these disorders are reversible. For example,
hypothyroidism, vitamin B-12 deficiency, and folic acid deficiency
can present with a mild degree of dementia. Patients with enlargement
of the ventricles in the brain present very much like AD. Those are
completely treatable. We teach medical students a list of 70 different
diseases that can present with dementia that mimics, more or less,
what AD looks like. So, everyone should have a very thorough work
up to search for the treatable causes of dementing diseases.
EL: If someone thinks they
or a member of their family has AD type symptoms, what should they do?
WM: They should be seen by
a neurologist and especially someone who’s interested in dementing
illnesses and have a very thorough work up.
EL: From what you’ve
said, it’s very difficult to diagnose AD.
WM: I don’t believe it
is difficult to diagnose AD, although there is no diagnostic test.
We do a thorough evaluation including an in-depth history, neurological
exam, mental status testing, blood studies, and MRI or CT scanning.
This evaluation also rules out (or in) treatable or reversible causes
of dementia. After you have excluded all other possible diagnoses,
we are left with the conclusion that this is AD. The only way to be
definite about the diagnosis of AD is to look at the brain under the
microscope after autopsy. In our center, where we follow patients
for many years and then do autopsies at death, we are 95 percent correct
in the clinical diagnosis. But that is to say we’re five percent
wrong – underscoring the need for a diagnostic clinical test.
EL: Are MRI studies part of
your ongoing research because that can denote changes in brain patterns?
WM: Yes, you can look at specific
brain areas such as the medial temporal lobe and the hippocampus and
they may show degenerative changes. They may not be specific, but
the MRI scan is a big help. The SPECT and PET scans are very helpful
in coming to a diagnosis.
EL: Why is the Sanders-Brown
Center on Aging considered to be one of the top research facilities
in America?
WM: Sanders-Brown has an excellent
faculty and staff. Our team has a strong work ethic and good ideas.
The fact that the Sanders-Brown Center on Aging has been funded by
the National Institutes of Health for 20 years indicates that we’re
a good center. Grants are reviewed by your peers and are extremely
competitive.
EL: What are the three main
sources of funding for COA research efforts?
WM: One is from research grants
and most of those are from the National Institutes of Health. The
second is private funding. The third is from University of Kentucky
funds, which allow COA to have buildings and equipment.
EL: How important are charitable
gifts to the Center?
WM: Private funding is extremely
important because it supports some of the research that we do. The
original Sanders-Brown building was the product of a gift from the
John Y. and Eleanor Brown foundation. It was matched by state and
UK funds.
EL: Do you anticipate any
new major breakthroughs in treating AD?
WM: When I was younger and
more naïve I said would be in five years; like I knew what I
was talking about. But we have a lot more hope now. We had great hope
for the amyloid vaccine, but that sort of fell by the wayside, at
least temporarily. But there are many drug trials in AD, some in which
our center is involved. The pharmaceutical industry is working hard
to find the ideal therapeutic agent and they have lots of resources
to invest. So the light at the end of the tunnel has gotten brighter
because we have a much richer understanding of the disease process
and its pathogenesis. Everyday we’re chipping away a little bit
more at what causes the disease. So I have great hope that over the
next 10 years we’ll be able to do more prevention or treat AD
much more effectively.
EL: Are smoking or alcoholic
beverages risk factors in AD?
WM: No one has proven that
alcohol is a risk factor. There are some studies in France that suggest
a little red wine may help prevent AD, but I don’t really believe
that.
Smoking does not appear to
be a risk factor as far as we know.
EL: You have been working
on AD at the COA for 23 years. What has motivated you to invest so much
of your time and energy in this effort?
WM: When I first started in
medicine I saw lots of patients with AD and it’s a very helpless
feeling to say “you’ve got a disease which we can’t
treat and can’t cure.” No one has ever recovered from AD.
AD looked like a problem that needed to be solved in the laboratory.
That may sound a little dramatic, but it was an opportunity to not
only study the most devastating disease that I know of, in the laboratory,
but also in humans. By being a neurologist and a neuropathologist,
that gave me an opportunity to use my training and skills. When you
get involved with patients and families, you really see what a devastating
disease it is. If you have any feelings at all you want to do something
about AD because it is the worst disease to affect human beings. Those
are some of my motivations.
EL: Dr. Thomas Clark, UK’s
oldest professor, just celebrated his 99th birthday and he’s been
selected as the Senior Kentuckian of the year by the Sanders-Brown Center
on Aging Foundation. Why was Dr. Clark selected for this recognition?
WM: It’s a marvelous
selection. Dr. Clark is a wonderful human being. He represents many,
many good things about the Commonwealth of Kentucky. He is someone
who represents healthy aging very, very well. And, he’s a man
with immense class. He shows how one can live life to its fullest.
EL: Would you like to comment
on the staff at Sanders-Brown?
WM: Our investigators and
staff at COA work well together; it’s been an excellent team
effort. We’ve had good chemistry while working together for the
common good on major problems in aging. The other thing is that the
University of Kentucky has been extremely supportive of the Center
on Aging. I feel very grateful to have the opportunity to work in
an institution that not only supports you, but also gives you the
opportunity to work in an exciting environment and be challenged everyday.
One of the meanings of life, I think, is to be challenged everyday.
And the amazing thing is, I get paid for doing something that I would
do for free.
EL: If someone wants to get
more information regarding AD, where is a good reference place for them
to start?
WM: The Information Transfer
Core at the Sanders-Brown Center on Aging sends out lots of information
about Alzheimer’s and dementing diseases.
Contact us at: Sanders-Brown
Center on Aging, 101 Sanders-Brown Building, University of Kentucky,
Lexington KY 40536-0230, 859-257-1412, Fax: 859-323-2866 or www.alzheimers.org.
Ed G. Lane is chief executive of Lane Consultants Inc. and publisher
of The Lane Report.
edlane@lanereport.com
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