The
National Institute on Aging (NIA) is launching a nationwide treatment
study targeting individuals with mild cognitive impairment (MCI),
a condition characterized by a memory deficit, but not dementia. The
start-up of the trial, announced at a news conference held in Washington,
D.C., coincides with publication of a separate NIA-funded study in
this month's issue of Archives of Neurology confirming
that MCI is different from both dementia and normal age-related changes
in memory. Accurate and early evaluation and treatment of MCI individuals
might prevent further cognitive decline, including development of
Alzheimer's disease (AD).
The
upcoming Memory Impairment Study is the first such AD prevention clinical
trial carried out by NIH, and will be conducted at 65-80 medical research
institutions located in the United States and Canada. This study will
test the usefulness of two drugs to slow or stop the conversion from
MCI to AD. The trial will evaluate placebo, vitamin E, and donepezil,
an investigational agent approved by the Food and Drug Administration
for another use. Vitamin E (alpha-tocopherol) is thought to have antioxidant
properties, and was shown in a 1997 study to delay important dementia
milestones, such as patients' institutionalization or progression
to severe dementia, by about seven months.
Participants
will be randomly assigned to one of the three groups. The study will
be carried out in 720 people over a 3-year period within the NIA's
consortium of AD clinical research centers, called the Alzheimer's
Disease Cooperative Study (ADCS). The study will be directed by Dr.
Ronald C. Petersen, Ph.D., M.D., of the Mayo Clinic in Rochester,
Minnesota, and Dr. Michael Grundman, M.D., M.P.H., of the University
of California at San Diego (UCSD). Dr. Leon Thal, M.D., of
UCSD, directs the ADCS.
"While
cognitive testing may reveal people with MCI to have a significant
memory problem, their other cognitive functions remain normal and
are for the most part unaffected by MCI," said Dr. Thal. "Prior
to today, most treatments tested for slowing memory decline have been
evaluated in patients with well-defined AD. What we hope to accomplish
in this trial is to test agents that delay or stop further memory
deterioration or the onset of AD in persons with MCI. In order to
do that, it is our hope that as many people as possible with specific
memory impairments volunteer to participate in this study."
In a
different study, Dr. Petersen and colleagues at the Mayo Clinic compared
the cognitive testing results of three groups of people: people with
MCI, patients with mild AD, and people with normal memory. On memory
measures, people with MCI performed worse than those with normal memory
and were much more similar to patients with AD. On other cognitive
measures, the MCI individuals were equivalent to people with normal
memory and better than the AD patients. Dr. Petersen's study
appears in the March 1999 issue of Archives of Neurology.
"These
results indicate that there are patients who have forgetfulness beyond
what one would expect for their age, but who do not have Alzheimer's
disease," says Dr. Petersen. "Patients with mild cognitive
impairment are at greater risk for AD, and being able to identify
this group of patients will aid our efforts to find treatment interventions."
Investigators
have long been interested in MCI in part because a significant number
of people over the age of 65 with the condition eventually develop
ADľas many as 12-15 percent of them per year (or about 40 percent
after 3 years). Only 1 percent per year (or 3 percent after 3 years)
of healthy people over the age of 65 develop AD. While individuals
who eventually develop dementia go through a phase of mild cognitive
impairment, some individuals with MCI may never convert to the clinical
stages of AD.
The
Memory Impairment Study targets people between the ages of 55 and
90. Those interested in participating in the clinical trial should
have a memory complaint, exhibit memory impairment in testing—but
be able to perform everyday activities normally—and should not
have a clinical diagnosis of Alzheimer's disease. Information
on patient recruitment for the trial is available by calling 1-888-455-0655
and at http://www.alz.ucsd.edu/mci/.
Normal
memory loss generally associated with aging is characterized by misplacing
an item, forgetting someone's name, or forgetting to pick up
something at the store. Memory loss associated with MCI is more severe
and involves continuing problems in delayed recall of information.
Abnormal memory loss, associated with dementia, is characterized by
even more severe problems, such as disorientation, an inability to
recall very recent events, and general confusion. A number of other
conditions, diseases, and medications can cause many of the symptoms
associated with dementia, making correct clinical evaluation essential.
"Before
now, evaluating people with MCI has been difficult because we haven't
had a clear definition of the symptoms of the disease," says
Dr. Marcelle Morrison-Bogorad, Ph.D., Associate Director of NIA for
the Neuroscience and Neuropsychology of Aging Program where the bulk
of the Federal Government's Alzheimer's disease research
is coordinated. "Now we can use information from Dr. Petersen's
study and related studies to identify people with MCI and to develop
ways to prevent or delay the onset of AD in this high-risk population.
To delay or prevent the slide from mild cognitive impairment to dementia,
even in a fraction of people, would have profound effects socially,
financially, and otherwise."
The
Memory Impairment Study is sponsored by the Alzheimer's Disease
Cooperative Study at the University of California, San Diego, with
grant funding from the National Institute on Aging and contributions
from Pfizer Inc. and Eisai Inc. Additional support is from Roche Vitamins
Inc.
The
NIA, one of 25 Institutes and Centers at the National Institutes of
Health, leads the Federal effort in studying Alzheimer's disease and
supporting basic, clinical, epidemiological and social research on
aging and on the special needs of older people.
Embargoed
for release March 15, 1999, 10:30 a.m. EST
1. What
is Mild Cognitive Impairment?
Mild
cognitive impairment (MCI) is a condition characterized by memory
impairment with otherwise unaffected cognitive functioning.
2.
How can MCI be distinguished from normal forgetfulness?
Normal
memory changes associated with aging are characterized by momentary
lapses, such as misplacing an item, forgetting someone's name,
or forgetting to pick up something at the store. In contrast, memory
loss associated with MCI is a more persistent and troublesome problem.
People with MCI have much greater difficulty, for example, remembering
a fact after a relatively short time. In cognitive testing, people
with MCI, after a delay, remember significantly less of a paragraph
they have read or details of simple drawings they have seen compared
to people with normal memory changes associated with aging. A person
with MCI is likely to forget important events repeatedly, while significant
information is retained in normal aging.
3.
What about MCI and dementia? Is there a relationship between MCI and
Alzheimer's disease?
As its
name indicates, MCI is a condition of mild impairment, specifically
in the area of memory, while dementia is characterized by additional
and severe problems in other areas of cognition, such as orientation,
language, and attention. Alzheimer's disease (AD) is the most
common form of dementia among people age 65 and older. While most
patients with MCI get worse, not all will. AD invariably results in
a gradual decline, eventually progressing to severe, debilitating
dementia.
Scientists
have been interested in MCI in part because a significant number of
people over the age of 65 with MCI eventually develop AD in some studies
approximately 12-15 percent of them per year (or about 40 percent
after three years). This is much higher than the 1 percent or so per
year in a normal population of people 65 and older. As such, MCI is
a risk factor for developing AD. Researchers are examining the possible
relationship between the two conditions.
4. How
is MCI diagnosed?
A new
report in the Archives of Neurology (March 1999), by Dr. Ronald
Petersen, et al., at the Mayo Alzheimer's Disease Center,
suggests that a diagnosis of MCI can be made on the basis of five
criteria: 1) memory complaints, 2) abnormal memory for age, 3) ability
to carry out normal activities of daily living, 4) normal general
cognitive function, and 5) no dementia. In this study, scientists
compared the cognitive test results of people with MCI to those of
healthy people and patients with mild AD. People with MCI typically
performed worse on the memory measures than healthy people, but scored
roughly the same as patients with AD.
However,
on other cognitive tests, measuring a person's disorientation
and confusion about routine activities, MCI individuals'
scores were equivalent to those of healthy people and better than
those of AD patients. MCI, therefore, represented a detectable failure
in memory in people with otherwise normal cognitive abilities. Before
now, evaluating people with MCI has been difficult because researchers
have had no agreed upon definition of the symptoms of the condition.
The findings by Petersen and colleagues and related studies can now
be used to help identify people with MCI. The study, primarily supported
by the National Institute on Aging (NIA), is part of ongoing efforts
to refine early clinical diagnosis of memory impairment and AD and
assess brain changes that occur. Ultimately, identifying people with
early memory changes will allow for timely intervention as therapies
are developed.
5. What
causes MCI, and does it run in families?
As with
AD, the causes of MCI remain unclear. No genetic link has yet been
found for the condition, although it is possible that, like AD, a
genetic component, might be a risk factor for people with MCI to develop
AD.
6. Why
is NIA supporting the Memory Impairment Study, and why now?
Studies
to date have looked at the effectiveness of drug treatments in the
stages of Alzheimer's disease when the condition is mild to moderate,
and when it has already interfered with daily function. By intervening
earlier -- before signs of memory impairment have developed into clinically
diagnosed AD -- scientists hope to delay the onset of AD or prevent
it altogether. The Memory Impairment Study is the first major prevention
trial for AD supported by NIA which is specifically designed to test
drug interventions in relatively healthy and well-functioning people.
7. What
is the Memory Impairment Study going to examine?
This
study will investigate the effectiveness of donepezil, a drug generally
prescribed for patients with mild to moderate AD, and vitamin E (alpha-tocopherol)
in delaying or preventing the onset of AD in people with mild cognitive
impairment. The Memory Impairment Study is sponsored by the Alzheimer's
Disease Cooperative Study (ADCS) headed by the University of California
at San Diego, with grant funding from the NIA and contributions from
Pfizer, Inc., and Eisai, Inc. Additional support is from Roche Vitamins,
Inc.
8.
Who will participate in the Memory Impairment Study? How many people
will participate? How will they be recruited?
Approximately
720 men and women ages 55 through 90 will be recruited for the 3-year,
multicenter study. The major requirements for participation in the
study include recent memory complaints, abnormal memory function on
standardized tests, good general health, and no clinical diagnosis
of AD. Some people may not be able to take part in the study. They
may have certain conditions that would exclude them from participation,
including: significant neurologic diseases such as Parkinson's
or Huntington's diseases; major depression; history of recent
alcohol or substance abuse; history of cancer or heart disease; recent
use of medications such as centrally active beta-blockers, narcotics,
or anti-convulsants; and any prior use of medications (Cognex, Aricept)
approved by the Food and Drug Administration (FDA) for the treatment
of AD.
The
Memory Impairment Study will be conducted by the ADCS, an established
nationwide network of research centers supported by the NIA and coordinated
by the University of California at San Diego. The ADCS sites will
be joined by other clinics and centers around this country and
Canada. Between 65 and 80 sites are expected to conduct the research.
A national participant recruitment campaign is planned, targeting
older people in cities where the study sites are located. Potential
study participants will be asked to call a toll free number, 1-888-455-0655,
at the ADCS central pre-screening agency. The callers initially will
be screened over the telephone for inclusion in the study. Those who
may qualify for participation will, in turn, be referred to study
sites in their area for additional screening.
9.
How much of a participant's time will be required for the study,
and what types of medical testing will the participants undergo?
Study
participants will visit their local clinical center about nine times
over a 3-year period, including the initial screening visit. Evaluations
of participants will begin at the second visit and continue every
3 months for the first 6 months, and then every 6 months for the remainder
of the 3 years, or until a clinical diagnosis of AD is made. Testing
will include neurological examinations (cognitive measures and clinical/functional
testing), blood and urine collection, medication compliance measures
(pill count and serum vitamin E levels), and a physical examination.
Participants will be closely monitored for side effects.
10.
Where is the study being conducted? How can people find out about
locations?
The
study will be conducted in at least 65 clinical centers throughout
the United States and Canada. Each center will enroll 12 to 36 participants.
It is important to note that for every participant accepted into the
study, many more volunteers will need to be screened. People can find
out more about their eligibility and about locations by calling toll
free 1-888-455-0655.
11.
Why were donepezil and vitamin E selected for this study? What dosages
will be used in the study? Are they the same amounts that people take
now?
Donepezil
is one of two drugs approved by the FDA (tacrine is the other) to
treat patients with mild to moderate AD. Donepezil helps prevent the
degradation of acetylcholine --a neurotransmitter (i.e., a
brain cell communication chemical) that is important for attention
and memory. Vitamin E is thought to have antioxidant properties, that
is, to counteract destructive damage from molecules called free radicals.
The progressive loss of brain cells that occurs in dementia and AD
may be related to this damage. In a previous ADCS study in 1997, also
supported by the NIA, vitamin E was shown to slow down functional
decline of patients with moderate AD by about seven months.
Study
participants will be assigned randomly to one of three groups, and
participants will receive donepezil, vitamin E, or a placebo (inactive
pill). The dosage of donepezil will be 5 mg per day for the first
6 weeks and then 10 mg until the end of the study, dosages similar
to those prescribed for patients with mild to moderate AD. The study's
dosage of vitamin E will be 1,000 IU (International Units) per day
for the first 6 weeks and then 2,000 IU per day until the end of the
study. This dosage is higher than the amount typically found in vitamin
supplements but was shown to be well tolerated with few side effects
in the 1997 study. Participants in the placebo group will receive
inactive pills similar in size to the other drugs being tested. All
study participants will receive a daily multivitamin.
The
Memory Impairment Study is designed to demonstrate the potential effectiveness
of each treatment in preventing or delaying the onset of AD. If any
participant receives a clinical diagnosis of AD before the end of
the study, the participant will be offered active donepezil until
three years have elapsed from the time of entry into the study.
12.
A lot of people are already taking vitamin E. Isn't it already
proven that vitamin E can improve health, and shouldn't people
be taking it anyway now?
As an
antioxidant, vitamin E is important in the body for stabilizing membranes
and protecting them against free radicals. Vitamin E was demonstrated
to slow some aspects of functional deterioration in patients with
AD in the 1997 study. However, this study has not yet been replicated.
The dose that will be used in the Memory Impairment Study is reasonably
high. Only a controlled clinical trial to determine safety and effectiveness
will answer whether this high dose, which the researchers believe
is needed to reduce oxidative damage in the brain, is helpful in possibly
preventing or delaying the onset of AD.
13.
Are there any side effects associated with donepezil or vitamin
E?
Donepezil
has shown no serious side effects during clinical trial testing for
FDA approval. No laboratory monitoring is currently mandated for the
drug by FDA. Donepezil has shown minimal effects on the liver; its
most common side effect is nausea.
In the
1997 study, a dosage of 2,000 IU per day of vitamin E was well tolerated
with few side effects. However, the long-term effects and potential
hazards of such high doses are unknown. In excessively large doses
(above 2,000 IU per day), vitamin E may be associated with increased
risk of bleeding in certain people. Some studies also have suggested
that high doses of vitamin E should not be used with anti-coagulant
medications. People are encouraged to consult their family doctors
before taking high doses of vitamin E as a supplement.
14.
How long will the Memory Impairment Trial take? When will the findings
be known?
The
study will last 3 years from the date of the second visit. Data analysis
will begin after two-thirds of the participants have completed the
study. The faster the recruitment phase, the more rapidly the study
will be completed, the results analyzed, and the findings made known.
15.
Where can I find out more about clinical trials for Alzheimer's
disease?
The
NIA supports a new clinical
trials database of promising compounds to treat AD. The database,
which is being developed cooperatively with the FDA, provides information
about AD clinical trials and sites and is designed to help encourage
participation in research. It describes study designs and explains
the possible modes of action of selected drugs. The database also
outlines eligibility criteria for participants and lists locations
and contact information for study sites. The database is available
at the NIA's Alzheimer's Disease Education and Referral
Center (ADEAR) website at www.alzheimers.org
or by telephone at 1-800-438-4380.
16.
Where can people get more general information about memory problems,
MCI, and Alzheimer's disease?
Additional
information is available from the NIA-funded Alzheimer's Disease
Education and Referral (ADEAR) Center at:
ADEAR
Center
PO Box 8250
Silver Spring, MD 20907-8250
1-800-438-4380
301-495-3334 (fax)
http://www.alzheimers.org
Information
is also available from the Alzheimer's Association at:
Alzheimer's
Association
919 N. Michigan Avenue
Suite 1000
Chicago, IL 60611-1676
1-800-272-3900
http://www.alz.org/
Prepared
by National Institute on Aging 3/9/99
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