Innovative therapies show promise for Alzheimer’s
Drug treatments and lifestyle-based interventions share spotlight at
first ever Alzheimer’s Association Prevention Conference
June 20, 2005
Washington, D.C. – A number of innovative treatment
possibilities — including a new version of an anti-inflammatory drug, a
low-intensity calisthenics program and what may be the next chapter in the
Alzheimer vaccine story — all show some promise for Alzheimer’s disease
as demonstrated by new research studies reported today at the first
Alzheimer’s Association International Conference on Prevention of
Dementia.
“We are very encouraged to see a diversity of approaches to treating
Alzheimer’s showing some level of success,” said Steven DeKosky, M.D.,
director of the Alzheimer’s Disease Research Center at the University of
Pittsburgh and a member of the Alzheimer’s Association Board of Directors.
“The urgency of developing better treatments for Alzheimer’s demands
that we pursue every available avenue.”
Several of the new treatment methods target beta amyloid, an abnormal
brain protein thought to have an important role in Alzheimer’s disease.
The abnormal protein collects into sticky bundles in the brain called
plaques. Investigators continue to study whether it is the beta amyloid
itself, some further modified form of the abnormal protein, or the plaques
that cause the death of brain cells in Alzheimer’s.
“Amyloid as a possible cause for Alzheimer’s is the most mature
theory of the disease, and must be thoroughly tested,” said William Thies,
Ph.D., Alzheimer’s Association vice president for Medical & Scientific
Affairs. “We need an answer to the amyloid question so that we can sharpen
our focus on amyloid and create better treatments and perhaps a cure, or
change our focus to other areas if the theory is wrong.”
Intravenous Immunoglobulin (IVIg) improves mental function in small
study
In 2002, the first trial attempting to focus the body’s own immune
response on beta amyloid through active immunization was halted due to brain
inflammation in about six percent of participants. To try to avoid these
side effects, some scientists are focusing on passive administration of
antibodies to beta amyloid in Alzheimer’s disease.
At the Alzheimer’s Association Prevention Conference, Marc Weksler,
M.D., Wright Professor of Medicine, and Norman Relkin, M.D., Ph.D., Director
of the Memory Disorders Program, at the Weill Medical College of Cornell
University, and colleagues reported on the use of intravenous immunoglobulin
(IVIg) in eight individuals with mild to moderate Alzheimer’s disease.
IVIg is a product derived from human donor blood that contains high
concentrations of antibodies, including antibodies to beta amyloid. It is
administered through an intravenous drip, much like a blood transfusion.
Participants in the study were treated for six months with various doses of
IVIg followed by a three-month period without IVIg therapy. Patients
received IVIg doses every week, every two weeks or once per month.
After each infusion of IVIg, the researchers found that levels of
anti-beta amyloid antibody in the plasma of all eight patients increased in
a dose-dependent fashion. Test of cerebrospinal fluid in each of the six
participants studied to date showed a lowering of beta amyloid to a greater
degree than previously observed – an average 45 percent decrease.
Cognitive function in the study participants was measured before and
after six months of IVIg therapy using the MMSE. None had lower scores after
the intervention than before, and in six of eight patients there was a
significant improvement after receiving IVIg.
“These results clearly justify further study in a larger,
placebo-controlled, double blind trial. However, our evidence does not
recommend IVIg as a current treatment for Alzheimer’s disease,” Weksler
said.
(R)-flurbiprofen encouraging in mild Alzheimer’s
(R)-flurbiprofen (Flurizan, Myriad Genetics), a single enantiomer of
flurbiprofen, has been shown to selectively lower brain levels of a toxic
form of beta amyloid (Aß42) in a model of Alzheimer’s. At the
Alzheimer’s Association Prevention Conference, researchers led by Gordon
Wilcock, Professor of Care of The Elderly and Head of the Bristol Dementia
Research Group, University of Bristol, UK, reported new results from the
first multi-center, placebo-controlled, double-blind study of (R)-flurbiprofen
in people. Participants in the 12-month trial received twice daily doses of
either 400 mg or 800 mg of drug, or placebo.
When results for all 207 participants were considered as a whole, (R)-flurbiprofen
showed a weak positive trend in helping individuals with mild Alzheimer’s
disease, though results did not reach statistical significance. The
researchers saw stronger positive trends when results for 128 participants
with mild Alzheimer’s were analyzed separately; though, again, these did
not reach statistical significance. Participants with mild Alzheimer’s who
were taking the highest dose of (R)-flurbiprofen did better than those
receiving the placebo on tests of memory and thinking skills, ability to
carry out daily activities, and overall function.
Study results were further subdivided to focus on participants with mild
Alzheimer’s taking the highest dose who also developed high levels of the
drug in their bloodstream. That group experienced a statistically
significant benefit in their ability to carry out daily activities and their
overall function, but not on measures of memory and thinking skills.
(R)-flurbiprofen is one of the three possible forms of flurbiprofen that
seems to have the greatest impact on beta-amyloid but has little or no
anti-inflammatory effect. (R)-flurbiprofen, unlike the other forms, is not
an NSAID (nonsteriodal anti-inflammatory drug); it does not inhibit the
cyclooxygenase (COX) enzyme as NSAIDS do. It is the COX inhibition aspect of
NSAIDs, such as with the combined form of flurbiprofen, that is associated
with side effects, including bleeding in the stomach and intestines and
increased risk of heart attack and stroke.
"There is little risk of stomach problems with (R)-flurbiprofen
because of the lack of COX inhibition in this form of the drug. The compound
has been shown to be well tolerated in healthy older volunteers at doses of
up to 1,600 milligrams per day in a phase I study and in this study,"
Wilcock said.
Intranasal insulin benefits Alzheimer patients with abnormal insulin
regulation
An increased risk of developing Alzheimer’s has been associated with
high blood insulin levels and reduced insulin effectiveness. These
conditions reduce the amount of insulin that reaches the brain, which may be
cause for concern given that insulin plays an important role in the
regulation of many chemicals and processes that support cognitive activity.
Insulin and other small proteins can be transported directly to the brain
through a nose-to-brain pathway, and intranasal insulin administration has
been shown to improve memory in younger adults.
In research also reported at the conference, Suzanne Craft, Ph.D., of the
University of Washington School of Medicine and the Veterans Affairs Puget
Sound Medical Center, and colleagues tested the hypothesis that intranasal
administration of insulin would enhance memory for adults with early
Alzheimer’s disease and amnestic mild cognitive impairment (MCI). They
also examined whether patients with Alzheimer’s who have a specific
genetic risk factor (known as ApoE4) would differ from patients without the
risk factor. Alzheimer patients without the risk factor are more likely to
have insulin abnormalities.
Twenty-six memory-impaired subjects (13 with early Alzheimer’s, 13 with
MCI) and 35 healthy older adults underwent three treatments consisting of
placebo or insulin (20 or 40 IU). The scientists found that insulin improved
recall of a story at both doses for patients without ApoE4, and also
improved their ability to remember a list of words at the higher insulin
dose. Normal adults and memory-impaired patients with ApoE4 showed no
improvement with insulin. Both AD and MCI patients responded similarly to
insulin.
“Our findings suggest that intranasal insulin administration may have
therapeutic benefit for adults with Alzheimer’s who have abnormal insulin
regulation,” Craft said. “Our findings also provide further evidence for
APOE-related differences in insulin metabolism in Alzheimer’s. Finally,
intranasal administration of other peptides should be explored as possible
therapeutic strategies for the treatment of Alzheimer’s.”
Herbal extract improves memory in people with MCI
In another study reported at the conference, Jinzhou Tian, M.D., Ph.D.,
of Dongzhimen Hospital at Beijing University of Chinese Medicine, and
colleagues found that an herbal extract known as GETO (from ginseng,
epimedium herb, thinleaf milkwort root and two other herbs), taken daily,
improved the memory of people with MCI.
In a randomized, double-blind study, 75 patients with MCI aged 65 years
and older were randomly assigned to a GETO group (given four GETO capsules
with two placebos), or a piracetam group (given two tablets of piracetam
with four placebos), or a placebo group (given six placebos), three times a
day for three months. Piracetam is a psychoactive drug that some believe may
improve cognitive function, but this theory has not been clinically tested.
All subjects received clinical assessments composed of a battery of
memory and learning tests at baseline, endpoint (three months), and
follow-up point (one year after treatment was stopped).
Researchers found that, overall, patients who took the GETO capsules
increased their cognitive function (measured by average MMSE score) from
27.5?1.7 at the start of the study to 28.3?1.7 after three months. Although
their average MMSE score showed a slight decrease to 26.9?1.9 at the one
year follow-up, this was still significantly higher than that those patients
who took placebo tablets (average 26.33?1.03). In addition, verbal learning
and recognizing abilities, and the total score for five-item memory
measures, increased significantly at a one-year follow-up point in patients
who took GETO capsules compared with those who took piracetam and placebo.
“This small preliminary clinical study shows that GETO extract capsule
may effectively improve memory function in patients with MCI,” Tian said.
“At this point, it is necessary to conduct a multiple-center clinical
trial of the efficacy and safety of GETO extract in patients with MCI.”
“The ingredients in GETO have been used to treat forgetfulness in
traditional Chinese medicine for centuries, and merit further study,” Tian
added. “Chinese herbal medicine is not only less expensive than standard
chemical medications, but also more readily accepted by Chinese elderly
people.”
Mild exercise program improves memory in elderly with MCI
A team led by Hideaki Soya, Ph.D., of the University of Tsukuba Graduate
School of Comprehensive Human Sciences, Tsukuba, Japan, sought to assess the
effect on cognitive functioning of an exercise intervention including mild
intensity calisthenics. Previous studies by this team had shown increased
blood flow to the prefrontal section of the brain during even mild intensity
exercise, which was enhanced when participants sang a favorite song.
The trial consisted of two types of exercise — a community-based
program offered up to six times per month with one hour of exercise, and a
home-based program of 10 to 60 minutes per day. The calisthenics, called
"Furfuri-Guppa," were combined with the singing of a favorite
song. The program was intentionally created to be simple, enjoyable, and of
mild intensity to encourage compliance. Memory function, peak torque of leg
extension, aerobic capacity, reaction time, and daily energy expenditure
were measured. Complete data was obtained on a group of 265 subjects with
normal cognitive function and MCI.
After one year of the exercise intervention, 70 percent of participants
showed significant improvement in memory function as measured on the 5-Cog
Test. Further, a significant correlation was found between the memory
function score and energy expenditure through Furfuri-Guppa®.
“It is of particular interest that the rate of memory improvement was
greater in participants with MCI than cognitively normal subjects,” Soya
said. “Though the exact reason is still uncertain, our program may have
the potential to delay cognitive decline and improve the physical fitness of
elderly people, including people with MCI.”
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