xt76hd7nsb72 https://exploreuk.uky.edu/dips/xt76hd7nsb72/data/mets.xml University of Kentucky. Office of the Vice President for Research and Graduate Studies Kentucky University of Kentucky. Office of the Vice President for Research and Graduate Studies 1998 volumes. Call Number: LD2762.9 .K38c. Accession Number: 2018ua049 journals LD2762.9 .K38c English Office of the Vice President for Research and Graduate Studies  Contact the Special Collections Research Center for information regarding rights and use of this collection University of Kentucky Odyssey Magazine Research -- Kentucky -- Periodicals Education -- Research -- Periodicals Research -- Kentucky Odyssey: The Magazine of University of Kentucky Research and Graduate Studies, Fall 1998 text images Odyssey: The Magazine of University of Kentucky Research and Graduate Studies, Fall 1998 1998 1998 2026 true xt76hd7nsb72 section xt76hd7nsb72  

 

Alzheimer’s: Fighting Back

 

  

UNlVERSlTY 1 i f ‘ce ()~ )6 ice refili en
OF KENTUCKY for Reslhfrt‘lh nridlfirjduat: Sitiijic;

O .10" Aclnunislrzitiun Building

1 niyvrsity (if Kermit l‘y
Lexington Kermit ky militants}
(“halo-1 lhiifi; l‘AV (“Kivlifi—lefi

hugs-raid H litanmell \nc Pursuit-m

Dear Friends of UK.

The University of Kentucky is now in the process of directing multimillion-dollar expenditures over the
next several years to enhance research programs and assist graduate students as a result of the 1997
Kentucky i’ostsecondary Education improvement Act.

The Research Challenge Trust Funds $16 million portion of. Lilxn's current operating budget comes from
a doli;tr—hrt»dollar match of funds provided through the Council on I’ostsecondary Education and from
reallocation ofuniversity funds. Research Challenge Trust Fund money will he used to support additional
faculty. graduate students and stall in eleven strong research programs. provide student-centered support
for the Graduate School, and for substantial lah renovations.

The research programs targeted by the university to receive additional faculty and stal’lare gerontology and
aging, advanced medical research. clinical pharmaceutical sciences research and graduate training,
molecular mechanisms of toxicity. computer science and electrical engineering, materiais synthesis, plant
sciences, biological chemistry. management and economics. psychology of substance abuse and preven—
tion, and geography.

The Graduate School is providing graduate assistant support packages in the form of 32 new graduate
fellowships and tuition assistance for 225 graduate research assistants in targeted programs of excellence.

UK has requested $17.5 million from a second incentive fund, the Research Equipment and Laboratory
Replacement Pool. With this investment we will he ahle to replace aging equipment with state-ohhe-art
instrumentation.

For now. we are investing our resources and concentrating our efforts on our most vaiuahle asset. out
peopie. in all. we are hiring 54 new faculty. supporting 87 graduate students as graduate assistant fellows,
adding technical support staff. and distributing 233 graduate assistant tuition scholarships.

UK‘s faculty, graduate assistants and staff will he the ones to advance our already prominent research

programs. Another record year of attracting $31.4 million in research contracts. grants and gifts proves
this fact. Together. with your continued support. we are moving forward to make a great university even
greater.

Yours truly.

Fitzgerald B. Bramweli

 

 

 

 

 

 

2 ()1) l'SSlz'Y

 

 

  

 

ODYSSEY

ALZHEIMER’S:
FIGHTING BACK

UK researchers are working at the cell level
to clzscoz/er t/se pat/aways oft/7e disease and bow to counter it

BY JEFF WORLEY

bout a quarter of a century ago, a new word
entered public usage: Alzheimer’s. Named

after the German physician Alois Alzheimer in
1907 and long—used in medical circles, the word
put a label on the dehumanizing condition of

degenerative memory loss and “

 

  

physical deterioration which ulti— i i q if

mately leads to death. An esti— ll: { i

mated 14 million Americans will 1 -

have Alzheimer’s by the year 2020. -;.
At the University of Kentucky, , ,,

researchers began working to understand this dis—

ease in the mid 19703, according to William

R1537:

 

/7/m7ul))‘/I'r'WWII/11h

WILLIAM
MARKESBERY,

ONE OF THE FIRST
SCIENTISTS AT

THE UNIVERSITY

OF KENTUCKY

To DO RESEARCH
INTo ALZHEIMER‘S
DISEASE, PERFORMS
AUTOPSIES ON
BRAINS DONATED To
UK's ALzHEIMER’s
DISEASE RESEARCH
CENTER. “ONLY
THROUGH AN
AUTOPSY OF THE
BRAIN CAN IT
DEFINITELY BE
DETERMINED
WHETHER SOMEONE
HAD ALIHEIMER’S
OR NOT."
MARKESBERY SAYS.

cu I; i z I: 1! e1!

1136]] .1.\[) (113:1!)IA'1‘15X'l'l [MISS 3

s: I; {9:134 v 4

 

  

 

Markesbery, director ofthe Sanders—Brown
Center on Aging. ul worked with Bill
Ehmann in the chemistry department here
for over 20 years, and we had our first grant
to study Alzheimer‘s in 1976 or ’77,”
M arkesbery recalls. “This was the first grant
at UK, and at this time there weren‘t many
grants around the country to study the
disease.”

In the 1960s and 19703 the study of
Alzheimer’s disease focused on describing
the effects ofthe disease, trying to describe
what Alzheimer’s “looked like.” “Back then
it was very descriptive,” Markesbery says,
“but all the descriptive work is behind us
and now were at the molecular level trying
to understand the mechanisms of the dis—
ease. And,” he adds, “it’s gotten to be very
exciting."

Markesbery is now a member of a re-
search team, which includes Chemistry Pro-
fessor Allan Butterfield and Mark Mattson,
a neurobiologist and professor at UK’s Sand—
ers—Brown Center on Aging. Four years ago
Butterfleld, Mattson andjohn Carney (then
a professor of pharmacology at UK) made
an exciting discovery that captured interna—
tional attention: they discovered how brain
cells are killed in the process ofAlzheimer’s
disease, a finding that National institute on
Aging director T. Franklin Williams called
a “breakthrough in the understanding of
the disease.”

Butterfield was instrumental in develop-
ing at that time what he called the “molecu—
lar shrapnel model" of brain cell death in
Alzheimer‘s disease.

“1 began thinking about the beta—amy—
ioid protein, a peptide [a series of amino
acids} that is the core block of abnormali—
ties in the brain called plaques,” says
Butterfield, who also directs UK’s Center
ofMembrane Sciences. “Plaques are one of
three features always found in the brains of
Alzheimer’s victims. The odd thing about
this peptide in plaques is that no matter
how you try to dissolve it, you can't do it. As

 

 

 

 

 

PHILIP LANDFIELD’S RESEARCH EXAMINES THE ROLE OF CALCIUM IN AGING

BRAINS. LANDFIELD AND COLLEAGUES HAVE FOUND THAT CALCIUM CHANNELS
INCREASE IN DENSITY AS THE BRAIN AGES, A CONDITION WHICH RESULTS IN A

GREATER INFLUX OF CALCIUM INTO THE CELLS OF AGING NEURONS.

a scientist, I asked myself, ‘How can you
account for this? The only answer I could
come up with is that the peptide was form—
ing covalent bonds—very strong chemical
associations. ‘And how are covalent bonds
formed?’ I asked. The answer that occurred
to me is by peptide free—radical reactions.”
Free radicals, Butterfield explains, are
molecules with one or more unpaired elec—
trons, an imbalance that causes them to be
extremely unstable and reactive. “Nature
abhors having unpaired electrons,” says
Butterfield. “50 free radicals are very reac-
tive because they are always trying to either
give up or accept an electron.”
Butterfield, Mattson and Carney set to
work immediately to see if they could detect
free—radical activity from the beta peptide.
Afterseveral control experiments using elec—
tron paramagnetic resonance spectroscopy,
the researchers found that this villainous

peptide was, in fact, associated with free
radicals. The free radicals attacked the cell
membranes, substantially damaging them.

Recent Findings about
Cell Membrane Death

That was four years ago. Armed with the
first theory that put Alzheimer’s disease
into an understandable and verifiable frame—
work, Butterfield, Mattson and Markesbery
(Carney left UK for a job in private indus—
try) subsequently found that the beta pep—
tide causes nerve cell damage by inducing a
free—radicaLmediated process called “lipid
peroxidation" in the nerve cell membrane.
Lipids are fatty or waxy substances which
constitute, along with proteins and carbo—
hydrates, one of the principal components
ofliving cells.

“We found that such lipid peroxidation
results in the impairment ofprotein func‘

 

 

4 () I) )‘SSEY

 

 

 

 

  

 

 

THE CROSS SECTION OF BRAIN BELOW IS FROM THE FRONTAL ANDTEMPORAL LOBES

OF A PATIENT‘S BRAIN THAT HAS LITERALLY BEEN WORN AWAY BY

ALZHEIMER’S DISEASE. THIS BRAIN SLICE IS CHARACTERIZED BY EN-

LARGED VENTRICLES (SPACES IN THE CENTER), AND SHRINKAGE OF THE
FOLDS AND WIDENING OF THE SPACES BETWEEN THE FOLDS OF THE
BRAIN INDICATING ATROPHY AND A SUBSTANTIAL LOSS OF GRAY
MATTER. THE OTHER CROSS SECTION (RIGHT) IS FROM A NORMAL
INDIVIDUAL. THIS SLICE SHOWS MUCH SMALLER VENTRICLES AND
MINIMAL ATROPHY OF THE GRAY MATTER.

tion in the membrane that
normally transports ions (so—
dium and calcium) out of
the cell and glucose into
the cell,“ says Mattson.
"This results in excessive
elevation of intracellular
calcium levels and reduced
levels and reduced energy
production in the neurons,
renderingthemvulnerableto
being “excited to death'"

Mattson saysthisfindingex—
plains the groups previous dis-
coveries showing that the beta
peptide disrupts calcium regulation in neu—
rons, making them sensitive to degenera—
non.

More recently, the researchers have fo—
cused on one of the products of the free—
radical attack, a molecule called
4«hydroxvnomenal, or HNE. This mol—

ecule was found to be elevated in Alzhei mer‘s

brains. The scientists believed that this
extremely reactive molecule, which targets
amino acids (the chief components ofpro—
teins) on the cell membrane, caused their
dysfunction. HNE, they thought, led to the
membrane being weakened, a condition
which subsequently allows calcium to leak
into the cell and kill it.

 

 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   

Mattson showed in 1996 that ifamyloid
is introduced into neuronal cells in culture
that HNE will be formed, and Butterfield
showed in 1997 that if HNE is added to
brain cells, the conformation of cell mem—
brane proteins will be changed.

“This finding confirmed an earlier dis—
covery ofours—amyloid‘s effect on various
transport proteins," says Butterfield. “This
was a very, very good finding," he adds.

uThis result, that amyloid was associated
with free radicals, also might explain an—
other enigmatic feature ofAlzheimers dis-
ease,"Butterf1eld says. "\Y'e see many reports
in the scientific literature ofdifferent prov
teins and lipids being altered in this dis
ease.“ Butterfield proposed that
amyloid—associated free radicals, being re-
active. would bind to these transport pro—
teins and alter their function in Alzheimer‘s
brain tissue.

“These free radicals also weaken the struc«
ture of membrane lipids," he says. "To—
gether. these free—radical—induced effects
on membranes might explain the altered
enzymes. transport proteins and lipids in
the brain.“

Most recently, the researchers have to
cused their attention on a molecule called
glutathione, a tri-peptide normally found
in everybodys cells. An important charac»
teristic ofthis molecule is that it naturally
counteracts HNE, preventing it from dam»
aging transmembrane proteins.

(UH/Illllt’t/ ur,‘ page i»

DURING THE LAST 10 YEARS. MARK
MATTSON HAS BECOME A LEADER IN
STUDIES OF MECHANISMS OF NEU-
RONAL DEREGULATION.

x’lz'.\‘/:'.1I\’(Ill .l.\l) (Mill)! .1715 NH HUN 5

 

  

 

USING
HIGH-PERFORMANCE
LIQUID CHROMA-
TOGRAPHY, ALLAN
BUTTERFIELD
SEPARATES
PEPTIDES FOUND

IN THE ALZHEIMER’S
DISEASE BRAIN.

“There’s

nothing
more
fiightening
for on
older person
than the

thought of

losing his
ability to
rememher
and to
thin/e and
to reason

clearly. ”

— W’illiam Markesbery

  
   

I
l

u\II/e have just completed a study in which we chemically
reduced the glutathione level in a living animal—we used
gerbils—with the question in mind: \X/ith a lowered glu—
tathione level, would the oxidated stress be worse than it would
be with the regular level of glutathione present?" Butterfield
says. “And the answer is yes. And then we turned the question
around: If we increase the glutathione level, would there be
increased protection? And the answer is, again, yes.”

This is an important discovery, Butterfield says, because it
means that the body’s natural antioxidant system might be used
to fend off free—radical damage. If the level of this molecule
could be significantly increased in our bodies, we would have a
natural system of damage control.

[r/Hi/i/ hr /<’I‘ llmmm

 

Calcium’s Role in Cell Death

In recent years calcium’s role in cell death
has been hypothesized by researchers. In
the early 19805 speculation began to grow
that aging alters the calcium balance and
this in turn makes the neurons more vul—
nerable for Alzheimer’s disease.

“It’s well known that calcium is critical to
a wide range of cellular processes,” says
Philip Landfield, UK professor of pharma-
cology. “But if calcium becomes, for some
reason, deregulated and the level rises, the
nerve cell will be gradually damaged be—
cause ofcalcium’s toxicity at higher levels.”
Landfield explains that calcium, a basic
mineral we get from some foods and milk,
is usually maintained at a very low level by
a series of buffering mechanisms and is
normally cleared rapidly from the cell.

Backed by a recent $1.4 million NIH
MERIT award and a $5 million program
project award from the National Institute
on Aging, Landfield and a team of scientists
at UK’s Chandler Medical Center are in-
vestigating calcium regulation in aged cells.
The effort includes multiple projects, based
primarily in pharmacology and the Sand—
ers-Brown Center on Aging.

“We received this MERIT award in part
because of our discovery here at UK that
there are more calcium channels in the
membranes of aged neurons,” Landfield
says. “We had the essential advanced tech-
nology here and the experienced research—
ers who’d been trained how to use it.”

The technology Landfield refers to be—
gins with a powerful microscope that allows
the viewer to observe the dissecting of a cell.
Using this microscope, Research Associate
Eric Blalock can view one nerve cell from an
aged rat and then—through a very precise
and delicate procedure—study the calcium
channels within that cell. Landfield ex—
plains: “Every membrane has channels in it.
Since we want to study only calcium chan-
nels, we introduce drugs known to react

 

6 ()1) I'SSE Y

 

 

 

 

  

 

with and block other types of channels.
Then we attach a small glass pipette with a
hole in the tip to the surface of" the nerve
cell. Now, what’s under the mouth of the
pipette is all that‘s recorded, the activity of
a single channel or single molecule.” A
series of blips—peaks and valleys—on a
printout records this channel opening and
closing.

\X’hen told that this all sounds extremely
complex and futuristic. Landfield says that
this observation is understandable and is
half right. It is difficult science, but the
method for exposing the cells has been
around “for all oliseven years or so now,“ he
says. adding that the scientists who devel-
oped this method won the Nobel Prize for
it in the early ")Os.

After the neurons channel activity is
recorded. the cell is pulled up by the pipette
and placed in a small test tube. It is then
taken to the lab next door. to Kuey—Chu
Chen, a research assistant professor. “We
want to analyze molecular contents of the
cell. but there‘s a problem," Landfield says.
"There‘s simply not enough material to
work with in one cell.“

That‘s where Chen comes in. Her job is
to take the DNA From the cell and through
a common technique called PCR (poly—
merase chain reaction) keep recycling (du—
plicating) the DNA until there's enough to
actually work with. This process amplifies
the genes in the cell just as turning up the
volume on a radio amplifies a song. The
result is what looks like, to the untrained
eye, a series of darker and darker smudges
displayed on a computer screen. These
marks tell the researchers how much DNA
is present to make proteins the researchers
want to study.

“This work focuses on one ofthe central
questions our group is trying to answer:
\X’hy are there more ofthese calcium chan—
nels in aging? There are two possibilities,"
Landfield says. “Either more channels are

t‘uIII/illrt'd UH page N

“In addition to ta/eing vitamin E
and vitamin C, measures can be
taken tofirestaiiA/zneimers dis-
ease. Yba snoala' restrietyoar a’i—

etaiy inta/ee to 1,600 to 2, 000

calories per day tnroagnoatyoar
adult life.”

7 Mark Mattson

 

PHILIP LANDFIELD’S
RESEARCH TEAM AND
COLLABORATORS ARE
INVESTIGATING THE
ROLE OF CALCIUM IN
CELL DEATH. FROM
LEFT To RIGHT:
(BACK Row)
LAWRENCE BREWER.
POSTDOCTORAL FEL-
Low IN THE BIOLOGY
OF AGING PROGRAM:
JEANISE STATON,
RESEARCH ASSIS-
TANT: CHRIS NORRIS.
POSTDOCTORAL
FELLow IN THE
DEPARTMENT OF
PHARMACOLOGY:
(FRONT Row) GREG
CLODFELTER.
GRADUATE STUDENT
IN PHARMACOLOGY:
ERIC BLALOCK. SE-
NIOR RESEARCH
ASSISTANT: AND
KUEY-CHU CHEN.
RESEARCH ASSISTANT
PROFESSOR.

lx’l',\/.l/\’( //.l\/) (IRAN/.1777 V'l'l l>llx\ 7

 

  

THIS SEQUENCE OF
PHOTOS SHOWS A
SINGLE BRAIN CELL
BEING RECORDED
AND THEN COL-
LECTED FOR MO-
LECULAR ANALYSIS.
IN A) A PATCH
PIPETTE IS USED TO
RECORD THE ELEC-
TRICAL ACTIVITY OF
THE NERVE CELL'S
CALCIUM CHANNELS.
B) THE NEURON IS
GENTLY PULLED
AWAY FROM THE
MAIN TISSUE SLICE.
C) THE NEURON IS
TRANSFERRED FROM
THE PATCH PIPETTE
TO THE HARVEST PI-
PETTE. THE HARVEST
PIPETTE IS REMOVED
FROM THE BATH AND
ITS CONTENTS
PLACED INTO A COL-
LECTION TUBE FOR
ANALYSIS OF THE
CELL'S PROFILE OF
GENE EXPRESSION.
THE RESEARCHERS
HOPE TO IDENTIFY
HOW GENES REGU-
LATE ACTIVITY OF
THE CELLS AND
EVENTUALLY DETER-
MINE HOW THIS GENE
EXPRESSION
CHANGES WITH
AGING.

8 ()/))\_\/;')

Harvest Pipette

 

Hi! the descriptive
work is behind as
and now we’re at t/oe
molecular level trying
to understand t/oe
mechanisms oft/7e
disease. And its
gotten to be very

- . »
€XCltl7lg.
— William Markesbery

being made or fewer are being broken down. Either way, it‘s a
deregulation problem that results in a buildup of calcium."
Further study ofthe amplified genes will lead to understanding
the activity ofthese calcium channels, Landfield says.

“Although PCR is an established technique, very few labs in
the world do this from a single cell,” says Landfield. “But this
single—cell amplification allows us to compare young cells with
old, to correlate the amount of different gene expression with
channel functions and determine the cells‘ vulnerability to being
killed.“

The ultimate goal is to determine which gene pathways are
involved in killing neurons. “What's unique about this work is
that we're using new techniques that are only beginning to be
available in basic biology and applying them to the problems of
brain aging."

Down the hall from Chen‘s lab, the calcium question is being
explored in another way. Olivier 'lihibault. an assistant research
professor, sits in a small semi—darkened room surrounded by an
impressive array ofequipment. A large microscope with numer—
ous attachments is complemented by two computers that cap—
ture different types of data on calcium. A TV screen records a
procession of peaks and valleys from. ilihibault explains, “the
currents from the nerve cell channels under scrutiny."

The pulses that translate on the screen are being recorded from
a pipette lodged in the center of the rat brain slice, which.
according to landfield, is a spot that will least affect the normal
firing of the cell. "Each time the cell fires, there‘s an electrical
change in the membrane, and it opens the calcium channel,"
Landfield explains.

Another screen shows the magnified neuron, some of it
glowing red. The red dye is a reagent added to the cell. \X’hen it
comes into contact with calcium, it glows red so that the
researchers can see where the calcium is in the cell, and how
much there is.

“This confocal laser scanning microscope can show us whether
there is calcium present in the cell and, beyond that, we can see
where the calcium is in different layers and levels within the cell,“
Thibault says. “It‘s very sensitive and difficult to use but is an
indispensable instrument for this kind of research.“ An advan—
tage to this approach, once it is mastered, Landfield says, is that
the electrical activity of young cells can be compared with that
of older cells, and the amount and location of calcium can be
compared. “It‘s a very powerful method for us to see calcium
influx at different depths in the cell," he says.

A few doors down the hall from where Thibault does his work,
the calcium question is being explored on another front. Nada
Porter, an assistant professor of pharmacology, and Veronique

 

 

 

 

  

 

’l'hihault Olivieer wife are working with

rat brain cells in culture. [his 1s a type of
f11st—for11ard research l’orrer explains be-
cause L'mbr10nic cells develop the same
changes in calcium channels in four to five
weeks in 11 I’etri dish 11s the animal itself
develops oVer a period of years.

“One clear advantage to this, ‘V Porter

sa1s is that since some of the same things

are happening in cell Lulture as happen in
the living animal 1Ve ma1 be able to reduce
the number of animals we are stud1ingand
focus mom on the calcium changes in cul—
ture that are most responsiblL for making
neurons vulnerable."

"Our strategy has been. and continues to
be. to bring the most advanced techniques
in the field to the study of‘aging." landfield
says. “\XVVe‘re using cutting-edge methodol—
ogy comparable with any in the world to
track down the key changes that cotne with
age to make 11 cell more vulnerable to
Alzheimers disease When I started on this
() 1Lars ago I f1gured it d take
about 10 years to sol1e the role of calcium
in aging 11nd cell death. 1 didn‘t realize how
long it would take just to test each aspect of
this. l guess l0 years always looks 11 lot
longer when it‘s in front of‘you rather than

behind you.VV

Alzheimer’s Disease
Research Today

rLseathZ

In contrast to the research climate for
Alzheimers 20 years ago there are now
hundreds of projects worldwide that are
focusing on the disease and how to under—
stand it 11nd control it. One reason for this
mushrooming of‘projects is that the largest
population group in the country theBab1
Boomers are now dealing firsthand with
the disease as they see mothers and fathers.
aunts and uncles, suffer 11nd die from
Alzheimeer. Other reasons include popu—
lation growth and longeVity.

“We just have so many more people
now," says Markesbery1 “and the elderly

 

 

generation is fairly outspoken and has a major political
impact on our congressional leaders. You know: there‘s
nothing more frightening for an older person than the
thouOhtof‘losinghisabilitv to rememberand to think and
reason clearly: so there s 11 large and vocal group of folks
in the over- 65 bracket lobbying ver1 strongl1 to do
something about this disease

Alzheimer s researchers are pleased about such groups
as the AARl’ (American Association of Retired Persons)
because the pressure they bring to bear on political leaders
translates directly into more federal funds for research
into Alzheimer's The money we get from agencies like
NIH also helps support graduate students 11nd post— docs
to be trained how to do good science says Butterfield

and Kentuckians should be proud that we re training
first— class students how to do f1rst— Llass science.

The short-term goal for Butterfield and his research
team is to continue to tr1 to understand the HNE
molecule to pinpoint its role in damaging health1 brain
cells. Butterheld sa1s the1 will better understand how
these cells die based 011 the free— radical model and how to
prL1ent that damage mostl1 through further exploration
of the glutathione molecule 11nd other brain— accessible
antioxidants.

“As 11 consequence were going to gain 11 lot more
insight into how to limit or prevent the damage associated
with Alzheimeer disease, our overall goal.“ Butterfield says.

11111/111111'1/1111

/1 (lg 1: m

KISS/1'. ll\’( 1/]

 

 

USING A CONFOCAL
LASER SCANNING
MICROSCOPE, OLIVIER
THIBAULT COMBINES
THE RESEARCH TECH-
NIQUES OF ELECTRO-
PHYSIOLOGY AND
IMAGING. TWO COMPUT-
ERS CAPTURE INFORMA-
TION ON THE CURRENTS
FROM THE NERVE CELL
CHANNELS UNDER
SCRUTINY. AND THE
AMOUNT AND LOCATION
OF CALCIUM IN RAT
CELLS.

1l.\l) (IV/(Al)! .1 TE .XV’I'I VIN/5S

/7|‘/11/'I1£1/I'HI‘IIL’

M11 1

9

 

  

Vitamin E’s Protective Role

There have already been payoffs from
Alzheimer’s research, including recent stud—
ies that show the effectiveness ofthe much-
heralded vitamin E to gobble up free radicals.
“\X’e’ve published two papers that show
vitamin E is protective against free—radical
damage,” says Butterfield. “And another
study, by a group of 12 clinical scientists
who published their work recently in the
New England journal ofMedieine, showed
that high—dose vitamin E given to late—stage
Alzheimer‘s patients prevented their insti—
tutionalization up to seven months. Such
studies are important in themselves and
also important to our work since this is
further proof that our concept about free—
radical oxidative stress may be accurate.n
High-dose vitamin E, he explains, means
2,000 units a day, which Butterfield says is
beyond what someone not afflicted with
Alzheimer’s should take. “Though I have to
toss out the caveat here to see your doctor
before deciding how much
vitamin E to take, I take a

reasonable to believe that we will soon be
delaying some of the more deleterious ef—
fects ofAlzheimer’s,“ Butterfield says. “And
ifyou could delay them for even a year or so,
think of the enormous benefit in terms of
lifestyle and daily living for these patients
and their families.”

Mattson, in a recently published article
which appeared in Science @Medz'ez’ne, speci—
fies what these “other therapies” are. “In
addition to taking vitamin E and vitamin
C, measures can be taken to forestall
Alzheimer’s disease,“ he says. “You should
restrict your dietary intake to 1,600 to
2,000 calories per day throughout your
adult life. Why? Because a number of
studies have shown that reducing calorie
intake also reduces cellular oxidative stress."

It‘s also important, Mattson says, to sus—
tain a high level ofintellectual activity and
vigorous phvsical activity. And postmeno—
pausal women he adds, should consider
estrogen replacement therapy.

“These recommendations probably

,homd m, 3 d3, my- An estimated 14 million

self.”

. s ' )
Markesbety,whobesides Amerzcems wzll leave Alz/mmers

being a researcher into disease by theyeflr 2020,

Alzheimer‘s is a well-re-

spected clinician, says that the strategy in
the ‘905 is to treat the disease before it starts
in those at risk, a sort of neuroprotective
therapy.

“Vitamin E is clearly beneficial if taken in
the right dosages,“ he says. “And there are
other compounds such as non—steroidal,
anti-inflammatory drugs. Estrogen seems
to slow free radicals down. And of course
we're working now on the possibility that
part of the body‘s own machinery—glu—
tathioneflcan fight off free‘radical dam—
age. And I‘m certain there are other things
that are going to come along, too.”

“\X’ith this recent news about vitamin E
and various other therapies. I think it‘s

10 ()1) l'XS/il'

sound familiar, because they are also the
approaches that reduce the risk ofdevelop—
ing cardiovascular disease and cancer,“
Mattson says. “The reason is straightfor—
ward. Cellular oxidative stress plays a major
role in all of these age—related disorders.
Reducing the level of oxidative stress re-
duces the risk of each disorder.u

 

THE BRAIN
DONATION
RESEARCH
PROJECT

ne Sunday David Wekstein’s home

telephone rang at 9 am, alerting

him that he and other researchers
at the University ofKentucky’s Alzheimer’s
Disease Research Center were about to
receive a special gift.

uYou don’t know me,” the caller told
Wekstein, who is the associate director of
the center, “but I‘m one of your control
subjects. My next—door neighbor is also one
ofyour controls. He just died two minutes
ago. Call me back at this number in about
live minutes. By then his sister will be here
and we'll get this thing going."

\Within an hour of that phone call, the
neighbor 5 body was on its way to the
University of Kentucky where researchers
would immediately perform an autopsy on
the man‘s brain. Both Wekstein’s caller and
his neighbor are part of a group of older
Fayette County residents who have agreed
to donate their healthy brains after they die
to help researchers learn more about
Alzheimer‘s disease.

Most agree to participate in the control
group because they have personal knowl-

edge ofAlzheimer 5 disease. They ve lost a
parent. spouse. sibling or another relative
or a friend to the disease, which afflicts an
estimated four million people in the United
States over the age of 65. including an
estimated 60,000 Kentuckians. Alzheimer‘s
disease is marked by progressive, irrevers—
ible declines in memory. performance of
routine tasks, time and space orientation,
language and communication skills, ab—
stract thinking. and the ability to learn and
carry out mathematical calculations. Other
symptoms include personality changes and
impairment of judgment.

Sinceitopened in 1985, UK‘sAlzheimer‘s
Disease Research Center has diagnosed and
followed hundreds of older people with
non—treatable memory disorders—almost
always Alzheimer's disease. The next ofkin
of many of the patients who are followed by
the Memory Disorders Clinic give permis—

 

 

  

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sion, when the patient dies, for an autopsy,
which must be done as quickly as possible
because ofbiochemical changes in the brain
after death, The autopsy serves two purn
poses: it lets the family know for sure ifthe
patient had Alzheimer’s disease, which can
be definitively diagnosed only through an
autopsy, and it allows the center to use the
brain for research. “It’s a way for us to
correlate what we find with the patient
clinically with what we find in the brain
after death,” Wekstein says.

But studying the brains of Alzheimer’s
patients alone was not enough. Researchers
needed a control group. “We can study
Alzheimer‘s brains for the next 20 years and
ifwe don't study brains ofpeople who don’t
have Alzheimer’s disease, we can’t draw
valid conclusions,“ Wekstein says.

So in August of 198‘) Wekstein began
recruiting people for a control group. The
Sanders—Brown Center on Aging already
had a pool of 1,200 older Fayette County
residents who were called on periodically
for research projects, and Wekstein began
writing letters to those volunteers 10 at a
time.

“Basically, it was a polite letter that said,
‘When you die,willyou give usyour brain.>m
Wekstein says. Phone calls followed the
letters. “Some of the people would pick up
the phone and say. ‘Hell. nol‘ And others
would politely say, “Thank you, but this is
not my thing,‘ and about 20 percent said,
“Yes, 1 would be very much interested,"‘
Wekstein recalls.

Researchers met with those who were
interested, explaining in detail what they
were obligating themselves to do and ask»
ing them to sign informed consents. The
researchers also administered neuropsycho»
logical tests to verify the volunteers nor»
malcy.

From those beginnings in 198‘), 49‘)
volunteers were recruited by the end of
May 1998, with 380 of them still being
followed (81 have died and a few have

plmlrr hi 1.1‘1’ l/mmm

 
 

DAVID
BRAIN
SINCE

WEKSTEIN HAS DIRECTED THE
DONATION RESEARCH PROJECT
IN 1989. “THE
PRIME MOTIVATION OF THE VOLUNTEERS
Is ALTRUISM,” HE SAYS.

ITS INCEPTION

either moved away or withdrawn from the
project). The center has not actively recruited
donors for several years because the group is
self—generating, with members of the group
recruiting their friends, says Gail Cohen, re—
search volunteer coordinator.

To join the control group, individuals must
be 60 or older (55 or older for people who have
a blood relative with Alzheimer’s disease), re—
side in the greater Lexington area, have normal
cognitive function as determined by neuropsy—
chological tests, have no history of neurologi»
cal or psychiatric disease, and have no history
of drug or alcohol abuse.

Researchers telephone